Details of Disease

General Information of Disease (ID: DIS7Y2EE)

• Disease Name: Leber hereditary optic neuropathy
• Synonyms: optic atrophy, Leber type; Lebers disease; LHON; Leber Hereditary optic atrophy; Leber optic atrophy; Leber's optic atrophy; Leber hereditary optic neuropathy; Leber's hereditary optic neuropathy
• Disease Class: 8C73: Mitochondrial myopathy
• Definition: Leber's hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease affecting the optic nerve and often characterized by sudden vision loss in young adult carriers.
• Disease Hierarchy:
  DIS1L24B: Eye degenerative disorder
  DISBHDU9: Familial dilated cardiomyopathy
  DISCV4E4: Hereditary optic atrophy
  DIS4DFBG: Hereditary optic neuropathy
  DISK7IP8: Mitochondrial oxidative phosphorylation disorder
  DIS7Y2EE: Leber hereditary optic neuropathy
• ICD Code:
  ICD-11: ICD-11: 8C73.Y
  Expand ICD-11: '8C73.Y
• Disease Identifiers:
  MONDO ID: MONDO_0010788
  MESH ID: D029242
  UMLS CUI: C0917796
  OMIM ID: 535000
  MedGen ID: 182973
  HPO ID: HP:0001112
  Orphanet ID: 104
  SNOMED CT ID: 58610003

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Idebenone	DMQFDRC	Approved	Small molecular drug	[1]

This Disease is Treated as An Indication in 1 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
GS010	DMYQDJG	Phase 3	NA	[2]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 11 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CRYZ	TTP6UO8	Limited	Biomarker	[3]
NPTX2	TTNJ5A6	Limited	Genetic Variation	[4]
AMD1	TTBFROQ	Strong	Genetic Variation	[5]
CEP290	TT3XBOV	Strong	Biomarker	[6]
GRIA2	TTWM461	Strong	Biomarker	[7]
GRM2	TTXJ47W	Strong	Biomarker	[7]
IL1A	TTPM6HI	Strong	Biomarker	[8]
OPA1	TTTU49Q	Strong	Biomarker	[9]
PGD	TTZ3IFB	Strong	Genetic Variation	[4]
RPE65	TTBOH16	Strong	Biomarker	[6]
RPGR	TTHBDA9	Strong	Genetic Variation	[6]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC26A5	DTPGHJ7	Strong	Genetic Variation	[10]

This Disease Is Related to 3 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NDUFS2	DEKX5CD	Supportive	Mitochondrial	[11]
FXN	DEXVHDB	Strong	Genetic Variation	[12]
NDUFS2	DEKX5CD	Strong	GermlineCausalMutation	[11]

This Disease Is Related to 28 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
DNAJC30	OTRZQJEG	Supportive	Mitochondrial	[13]
NDUFS2	OTBT8KW9	Supportive	Mitochondrial	[11]
COX1	OTG3O9BN	moderate	Genetic Variation	[14]
ND4	OT4RQVAA	moderate	Biomarker	[15]
ADI1	OT8IOD03	Strong	Genetic Variation	[16]
AIPL1	OT4VBD78	Strong	Genetic Variation	[17]
ATP6	OTPHOGLX	Strong	Genetic Variation	[18]
BNIP3L	OTJKOMXE	Strong	Genetic Variation	[19]
COX3	OTNNGBYJ	Strong	Genetic Variation	[20]
CYTB	OTAHB98A	Strong	Genetic Variation	[21]
ENDOG	OT5IM7B3	Strong	Biomarker	[22]
GCA	OTAJ7ZHG	Strong	Biomarker	[23]
GLIS3	OTBC960E	Strong	Genetic Variation	[24]
GMCL1	OTRZHUFV	Strong	Biomarker	[23]
IMMT	OTBDSLE7	Strong	Genetic Variation	[25]
KRT10	OTSVRD3Q	Strong	Genetic Variation	[26]
LRAT	OTB7CJKY	Strong	Biomarker	[27]
ND2	OTG9OHOX	Strong	Genetic Variation	[28]
ND5	OT45LW1K	Strong	Genetic Variation	[29]
NDUFA1	OTKBUQXP	Strong	Genetic Variation	[30]
NDUFB11	OTFG5777	Strong	Genetic Variation	[31]
OPA3	OT6NDC1M	Strong	Genetic Variation	[32]
PHLDA2	OTMV9DPP	Strong	Biomarker	[33]
RP2	OTK050I3	Strong	Genetic Variation	[34]
RPGRIP1	OTABESO9	Strong	Genetic Variation	[35]
TK2	OTS1V4XB	Strong	Genetic Variation	[36]
MT-ND1	OTCLGIXV	Definitive	Mitochondrial	[37]
ND6	OTG47B7B	Definitive	Genetic Variation	[38]

References

• [1] Leber Hereditary Optic Neuropathy. 2000 Oct 26 [updated 2021 Mar 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy.Eur J Hum Genet. 2013 Jan;21(1):62-8. doi: 10.1038/ejhg.2012.112. Epub 2012 Jun 6.
• [4] PGD to reduce reproductive risk: the case of mitochondrial DNA disorders.Hum Reprod. 2008 Nov;23(11):2392-401. doi: 10.1093/humrep/den290. Epub 2008 Jul 29.
• [5] Characterization of retinal and blood mitochondrial DNA from age-related macular degeneration patients.Invest Ophthalmol Vis Sci. 2010 Aug;51(8):4289-97. doi: 10.1167/iovs.09-4778. Epub 2010 Mar 31.
• [6] Gene therapy and genome surgery in the retina.J Clin Invest. 2018 Jun 1;128(6):2177-2188. doi: 10.1172/JCI120429. Epub 2018 Jun 1.
• [7] Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber's Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells.Cells. 2019 Jun 21;8(6):625. doi: 10.3390/cells8060625.
• [8] Cytokine expression in the muscle of HIV-infected patients: evidence for interleukin-1 alpha accumulation in mitochondria of AZT fibers. Ann Neurol. 1994 Nov;36(5):752-8. doi: 10.1002/ana.410360511.
• [9] The idebenone metabolite QS10 restores electron transfer in complex I and coenzyme Q defects.Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):901-908. doi: 10.1016/j.bbabio.2018.04.006. Epub 2018 Apr 22.
• [10] Posterior reversible encephalopathy syndrome in a leber hereditary optic neuropathy patient with mitochondrial DNA 11778G>A point mutation.J Neuroophthalmol. 2013 Sep;33(3):276-8. doi: 10.1097/WNO.0b013e31828f8d75.
• [11] Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy. J Med Genet. 2017 May;54(5):346-356. doi: 10.1136/jmedgenet-2016-104212. Epub 2016 Dec 28.
• [12] Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders.Biochim Biophys Acta. 2009 May;1787(5):518-28. doi: 10.1016/j.bbabio.2009.02.024. Epub 2009 Mar 5.
• [13] Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. J Clin Invest. 2021 Mar 15;131(6):e138267. doi: 10.1172/JCI138267.
• [14] A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I.Am J Hum Genet. 1992 Aug;51(2):378-85.
• [15] Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.Clin Exp Ophthalmol. 2019 Aug;47(6):774-778. doi: 10.1111/ceo.13515. Epub 2019 May 8.
• [16] Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder.Am J Hum Genet. 2005 Dec;77(6):1086-91. doi: 10.1086/498176. Epub 2005 Oct 11.
• [17] The Leber congenital amaurosis protein AIPL1 modulates the nuclear translocation of NUB1 and suppresses inclusion formation by NUB1 fragments.J Biol Chem. 2004 Nov 12;279(46):48038-47. doi: 10.1074/jbc.M407871200. Epub 2004 Aug 30.
• [18] Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light.Hum Mutat. 2019 Dec;40(12):2430-2443. doi: 10.1002/humu.23885. Epub 2019 Aug 26.
• [19] Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.Acta Biochim Pol. 2019 Oct 4;66(4):427-435. doi: 10.18388/abp.2019_2837.
• [20] Mitochondrial DNA mutations in Cuban optic and peripheral neuropathy.J Neuroophthalmol. 1994 Sep;14(3):135-40.
• [21] Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.Am J Hum Genet. 2007 Aug;81(2):228-33. doi: 10.1086/519394. Epub 2007 Jun 4.
• [22] Caspase-independent death of Leber's hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G.Apoptosis. 2005 Oct;10(5):997-1007. doi: 10.1007/s10495-005-0742-5.
• [23] Macular Retinal Sublayer Thicknesses in G11778A Leber Hereditary Optic Neuropathy.Ophthalmic Surg Lasers Imaging Retina. 2016 Sep 1;47(9):802-10. doi: 10.3928/23258160-20160901-02.
• [24] Analysis of the pathogenic human mitochondrial mutation ND1/3460, and mutations of strictly conserved residues in its vicinity, using the bacterium Paracoccus denitrificans.Biochemistry. 1998 Aug 25;37(34):11792-6. doi: 10.1021/bi9810555.
• [25] A neurodegenerative perspective on mitochondrial optic neuropathies.Acta Neuropathol. 2016 Dec;132(6):789-806. doi: 10.1007/s00401-016-1625-2. Epub 2016 Sep 30.
• [26] Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy.Am J Med Genet A. 2017 Nov;173(11):3093-3097. doi: 10.1002/ajmg.a.38403. Epub 2017 Sep 25.
• [27] Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis. Am J Ophthalmol. 2006 Oct;142(4):702-4. doi: 10.1016/j.ajo.2006.04.057.
• [28] Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.Genetics. 1992 Jan;130(1):163-73. doi: 10.1093/genetics/130.1.163.
• [29] Leber's hereditary optic neuropathy (LHON)-associated ND5 12338T?C mutation altered the assembly and function of complex I, apoptosis and mitophagy.Hum Mol Genet. 2018 Jun 1;27(11):1999-2011. doi: 10.1093/hmg/ddy107.
• [30] The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I.Hum Mol Genet. 2006 Sep 1;15(17):2543-52. doi: 10.1093/hmg/ddl176. Epub 2006 Jul 18.
• [31] The NDUFB11 gene is not a modifier in Leber hereditary optic neuropathy.Biochem Biophys Res Commun. 2007 Mar 30;355(1):181-7. doi: 10.1016/j.bbrc.2007.01.140. Epub 2007 Feb 2.
• [32] Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy.PLoS One. 2017 Jan 12;12(1):e0170090. doi: 10.1371/journal.pone.0170090. eCollection 2017.
• [33] Choroidal thickness and the retinal ganglion cell complex in chronic Leber's hereditary optic neuropathy: a prospective study using swept-source optical coherence tomography.Eye (Lond). 2020 Sep;34(9):1624-1630. doi: 10.1038/s41433-019-0695-5. Epub 2019 Dec 5.
• [34] Novel mutation in RP2 gene in two brothers with X-linked retinitis pigmentosa and mtDNA mutation of leber hereditary optic neuropathy who showed marked differences in clinical severity.Am J Ophthalmol. 2000 Sep;130(3):357-9. doi: 10.1016/s0002-9394(00)00553-5.
• [35] The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase.Hum Mol Genet. 2011 Sep 15;20(18):3592-605. doi: 10.1093/hmg/ddr280. Epub 2011 Jun 17.
• [36] Beyond cervical lipomas: myoclonus, gait disorder and multisystem involvement leading to mitochondrial disease.BMJ Case Rep. 2017 Jun 19;2017:bcr2016218861. doi: 10.1136/bcr-2016-218861.
• [37] Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet. 1991 May;48(5):935-42.
• [38] Personalized pediatric ophthalmology: a case report.J AAPOS. 2019 Aug;23(4):234-236. doi: 10.1016/j.jaapos.2019.03.003. Epub 2019 May 23.