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Autosomal dominant optic atrophy plus syndrome

MedGen UID:
976364
•Concept ID:
CN293505
•
Disease or Syndrome
Synonym: ADOA plus
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Related genes: OPA1, ATP1A3
 
Monarch Initiative: MONDO:0014720
Orphanet: ORPHA1215

Definition

A rare neuro-ophthalmological disease associating the typical optic atrophy with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia, ataxia and peripheral neuropathy. More rarely, other manifestations have been associated with this condition, such as spastic paraplegia or multiple-sclerosis like illness. [from ORDO]

Recent clinical studies

Etiology

A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.
Grau T, Burbulla LF, Engl G, Delettre C, Delprat B, Oexle K, Leo-Kottler B, Roscioli T, Krüger R, Rapaport D, Wissinger B, Schimpf-Linzenbold S
J Med Genet 2013 Dec;50(12):848-58. Epub 2013 Oct 17 doi: 10.1136/jmedgenet-2013-101774. PMID: 24136862
Multi-system neurological disease is common in patients with OPA1 mutations.
Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF
Brain 2010 Mar;133(Pt 3):771-86. Epub 2010 Feb 15 doi: 10.1093/brain/awq007. PMID: 20157015Free PMC Article
Costeff optic atrophy syndrome: new clinical case and novel molecular findings.
Ho G, Walter JH, Christodoulou J
J Inherit Metab Dis 2008 Dec;31 Suppl 2:S419-23. Epub 2008 Nov 7 doi: 10.1007/s10545-008-0981-z. PMID: 18985435
Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome.
Nicolaides P, Appleton RE, Fryer A
J Med Genet 1996 May;33(5):419-21. doi: 10.1136/jmg.33.5.419. PMID: 8733056Free PMC Article

Diagnosis

WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.
Hu K, Zatyka M, Astuti D, Beer N, Dias RP, Kulkarni A, Ainsworth J, Wright B, Majander A, Yu-Wai-Man P, Williams D, Barrett T
J Med Genet 2022 Jan;59(1):65-74. Epub 2021 May 18 doi: 10.1136/jmedgenet-2020-107257. PMID: 34006618Free PMC Article
OPA1 analysis in an international series of probands with bilateral optic atrophy.
Liskova P, Tesarova M, Dudakova L, Svecova S, Kolarova H, Honzik T, Seto S, Votruba M
Acta Ophthalmol 2017 Jun;95(4):363-369. Epub 2016 Nov 17 doi: 10.1111/aos.13285. PMID: 27860320
Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
Bonifert T, Karle KN, Tonagel F, Batra M, Wilhelm C, Theurer Y, Schoenfeld C, Kluba T, Kamenisch Y, Carelli V, Wolf J, Gonzalez MA, Speziani F, Schüle R, Züchner S, Schöls L, Wissinger B, Synofzik M
Brain 2014 Aug;137(Pt 8):2164-77. Epub 2014 Jun 25 doi: 10.1093/brain/awu165. PMID: 24970096Free PMC Article
Autosomal dominant hereditary optic neuropathy (ADOA): a review of the genetics and clinical manifestations of ADOA and ADOA+.
Skidd PM, Lessell S, Cestari DM
Semin Ophthalmol 2013 Sep-Nov;28(5-6):422-6. doi: 10.3109/08820538.2013.825296. PMID: 24138050
Costeff optic atrophy syndrome: new clinical case and novel molecular findings.
Ho G, Walter JH, Christodoulou J
J Inherit Metab Dis 2008 Dec;31 Suppl 2:S419-23. Epub 2008 Nov 7 doi: 10.1007/s10545-008-0981-z. PMID: 18985435

Therapy

Targeting DRP1 with Mdivi-1 to correct mitochondrial abnormalities in ADOA+ syndrome.
Lin Y, Wang D, Li B, Wang J, Xu L, Sun X, Ji K, Yan C, Liu F, Zhao Y
JCI Insight 2024 Jun 25;9(15) doi: 10.1172/jci.insight.180582. PMID: 38916953Free PMC Article
Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations.
Aleo SJ, Del Dotto V, Fogazza M, Maresca A, Lodi T, Goffrini P, Ghelli A, Rugolo M, Carelli V, Baruffini E, Zanna C
Hum Mol Genet 2021 Jan 21;29(22):3631-3645. doi: 10.1093/hmg/ddaa244. PMID: 33231680Free PMC Article

Prognosis

Unraveling the genetic spectrum of inherited deaf-blindness in Portugal.
Machado T, Cortinhal T, Carvalho AL, Teixeira-Marques F, Silva R, Murta J, Marques JP
Orphanet J Rare Dis 2025 Jan 14;20(1):22. doi: 10.1186/s13023-025-03542-5. PMID: 39806488Free PMC Article
Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome.
Nicolaides P, Appleton RE, Fryer A
J Med Genet 1996 May;33(5):419-21. doi: 10.1136/jmg.33.5.419. PMID: 8733056Free PMC Article

Clinical prediction guides

OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.
Zanfardino P, Amati A, Doccini S, Cox SN, Tullo A, Longo G, D'Erchia A, Picardi E, Nesti C, Santorelli FM, Petruzzella V
Hum Mol Genet 2024 Apr 18;33(9):768-786. doi: 10.1093/hmg/ddae008. PMID: 38280232
Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models.
Del Dotto V, Fogazza M, Musiani F, Maresca A, Aleo SJ, Caporali L, La Morgia C, Nolli C, Lodi T, Goffrini P, Chan D, Carelli V, Rugolo M, Baruffini E, Zanna C
Biochim Biophys Acta Mol Basis Dis 2018 Oct;1864(10):3496-3514. Epub 2018 Aug 4 doi: 10.1016/j.bbadis.2018.08.004. PMID: 30293569
OPA1 analysis in an international series of probands with bilateral optic atrophy.
Liskova P, Tesarova M, Dudakova L, Svecova S, Kolarova H, Honzik T, Seto S, Votruba M
Acta Ophthalmol 2017 Jun;95(4):363-369. Epub 2016 Nov 17 doi: 10.1111/aos.13285. PMID: 27860320
Optic atrophy plus phenotype due to mutations in the OPA1 gene: two more Italian families.
Ranieri M, Del Bo R, Bordoni A, Ronchi D, Colombo I, Riboldi G, Cosi A, Servida M, Magri F, Moggio M, Bresolin N, Comi GP, Corti S
J Neurol Sci 2012 Apr 15;315(1-2):146-9. Epub 2011 Dec 22 doi: 10.1016/j.jns.2011.12.002. PMID: 22197506Free PMC Article
The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype.
Rouzier C, Bannwarth S, Chaussenot A, Chevrollier A, Verschueren A, Bonello-Palot N, Fragaki K, Cano A, Pouget J, Pellissier JF, Procaccio V, Chabrol B, Paquis-Flucklinger V
Brain 2012 Jan;135(Pt 1):23-34. Epub 2011 Dec 20 doi: 10.1093/brain/awr323. PMID: 22189565

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