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Autosomal dominant optic atrophy classic form(OPA1)

MedGen UID:
137902
Concept ID:
C0338508
Disease or Syndrome
Synonyms: Kjer-type optic atrophy; OPA1; Optic Atrophy Type 1; Optic atrophy, juvenile
SNOMED CT: Autosomal dominant optic atrophy classic form (717336005); Autosomal dominant optic atrophy Kjer type (717336005); Kjer optic atrophy (717336005); Optic atrophy type 1 (717336005)
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.
 
Gene (location): OPA1 (3q29)
 
Monarch Initiative: MONDO:0008134
OMIM®: 165500
Orphanet: ORPHA98673

Disease characteristics

Excerpted from the GeneReview: Optic Atrophy Type 1
Optic atrophy type 1 (OPA1, or Kjer type optic atrophy) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity (usually between ages 4 and 6 years), visual field defects, and color vision defects. Visual impairment is usually moderate (6/10 to 2/10), but ranges from mild or even insignificant to severe (legal blindness with acuity <1/20). The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Other findings can include auditory neuropathy resulting in sensorineural hearing loss that ranges from severe and congenital to subclinical (i.e., identified by specific audiologic testing only). Visual evoked potentials are typically absent or delayed; pattern electroretinogram shows an abnormal N95:P50 ratio. Tritanopia is the classic feature of color vision defect, but more diffuse nonspecific dyschromatopsia is not uncommon. Ophthalmoscopic examination discloses temporal or diffuse pallor of the optic discs, sometimes associated with optic disc excavation. The neuroretinal rim shows some pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. [from GeneReviews]
Authors:
Cécile Delettre-Cribaillet  |  Christian P Hamel  |  Guy Lenaers   view full author information

Additional descriptions

From OMIM
Autosomal dominant optic atrophy is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, color vision deficits, and centrocecal scotoma of variable density (Votruba et al., 1998). Some patients with mutations in the OPA1 gene may also develop extraocular neurologic features, such as deafness, progressive external ophthalmoplegia, muscle cramps, hyperreflexia, and ataxia; see 125250. There appears to be a wide range of intermediate phenotypes (Yu-Wai-Man et al., 2010). Yu-Wai-Man et al. (2009) provided a detailed review of autosomal dominant optic atrophy and Leber hereditary optic neuropathy (LHON; 535000), with emphasis on the selective vulnerability of retinal ganglion cells to mitochondrial dysfunction in both disorders. Genetic Heterogeneity of Optic Atrophy Also see optic atrophy-2 (OPA2; 311050), mapped to chromosome Xp11.4-p11.21; OPA3 (165300), caused by mutation in the OPA3 gene (606580) on chromosome 19q13; OPA4 (605293), mapped to chromosome 18q12.2-q12.3; OPA5 (610708), caused by mutation in the DNM1L gene (603850) on chromosome 12p11; OPA6 (258500), mapped to chromosome 8q21-q22; OPA7 (612989), caused by mutation in the TMEM126A gene (612988) on chromosome 11q14; OPA8 (616648), mapped to chromosome 16q21-q22; OPA9 (616289), caused by mutation in the ACO2 gene (100850) on chromosome 22q13; OPA10 (616732), caused by mutation in the RTN4IP1 gene (610502) on chromosome 6q21; OPA11 (617302), caused by mutation in the YME1L1 gene (607472) on chromosome 10p12; OPA12 (618977), caused by mutation in the AFG3L2 gene (604581) on chromosome 18p11; OPA13 (165510), caused by mutation in the SSBP1 gene (600439) on chromosome 7q34; OPA14 (620550), caused by mutation in the MIEF1 gene (615497) on chromosome 22q13; OPA15 (620583), caused by mutation in the MCAT gene (614479) on chromosome 22q13; and OPA16 (620629), caused by mutation in the MECR gene (608205) on chromosome 1p35.  http://www.omim.org/entry/165500
From MedlinePlus Genetics
Optic atrophy type 1 is a condition that often causes slowly worsening vision, usually beginning in childhood. People with optic atrophy type 1 typically experience a narrowing of their field of vision (tunnel vision). Affected individuals gradually lose their sight as their field of vision becomes smaller. Both eyes are usually affected equally, but the severity of the vision loss varies widely, even among affected members of the same family, ranging from nearly normal vision to complete blindness.

In addition to vision loss, people with optic atrophy type 1 frequently have problems with color vision (color vision deficiency) that make it difficult or impossible to distinguish between shades of blue and green.

In the early stages of the condition, individuals with optic atrophy type 1 experience a progressive loss of certain cells within the retina, which is a specialized light-sensitive tissue that lines the back of the eye. The loss of these cells (known as retinal ganglion cells) is followed by the degeneration (atrophy) of the nerves that relay visual information from the eye to the brain (optic nerves), which results in further vision loss. Atrophy causes these nerves to have an abnormally pale appearance (pallor), which can be seen during an eye examination.  https://medlineplus.gov/genetics/condition/optic-atrophy-type-1

Clinical features

From HPO
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Abnormal amplitude of pattern reversal visual evoked potentials
MedGen UID:
871342
Concept ID:
C4025834
Finding
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
Abnormally pale skin.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Central scotoma
MedGen UID:
57750
Concept ID:
C0152191
Finding
An area of depressed vision located at the point of fixation and that interferes with central vision.
Red-green dyschromatopsia
MedGen UID:
102324
Concept ID:
C0155016
Disease or Syndrome
Difficulty with discriminating red and green hues.
Blue color blindness
MedGen UID:
57827
Concept ID:
C0155017
Disease or Syndrome
Tritanopia is an autosomal dominant disorder of human vision characterized by a selective deficiency of blue spectral sensitivity (Weitz et al., 1992).
Progressive external ophthalmoplegia
MedGen UID:
102439
Concept ID:
C0162674
Disease or Syndrome
Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).\n\nWhen the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.\n\nAlthough muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.\n\nProgressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.
Centrocecal scotoma
MedGen UID:
82870
Concept ID:
C0271196
Finding
A scotoma (area of diminished vision within the visual field) located between the central point of fixation and the blind spot with a roughly horizontal oval shape.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAutosomal dominant optic atrophy classic form
Follow this link to review classifications for Autosomal dominant optic atrophy classic form in Orphanet.

Professional guidelines

PubMed

Newman NJ, Yu-Wai-Man P, Biousse V, Carelli V
Lancet Neurol 2023 Feb;22(2):172-188. Epub 2022 Sep 22 doi: 10.1016/S1474-4422(22)00174-0. PMID: 36155660
Ferro Desideri L, Traverso CE, Iester M
Drugs Today (Barc) 2022 Nov;58(11):547-552. doi: 10.1358/dot.2022.58.11.3448291. PMID: 36422516
Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF
Eye (Lond) 2014 May;28(5):521-37. Epub 2014 Mar 7 doi: 10.1038/eye.2014.37. PMID: 24603424Free PMC Article

Recent clinical studies

Etiology

Paprocka J, Jezela-Stanek A, Śmigiel R, Walczak A, Mierzewska H, Kutkowska-Kaźmierczak A, Płoski R, Emich-Widera E, Steinborn B
Genes (Basel) 2023 Apr 25;14(5) doi: 10.3390/genes14050972. PMID: 37239332Free PMC Article
Cartes-Saavedra B, Lagos D, Macuada J, Arancibia D, Burté F, Sjöberg-Herrera MK, Andrés ME, Horvath R, Yu-Wai-Man P, Hajnóczky G, Eisner V
Proc Natl Acad Sci U S A 2023 Mar 21;120(12):e2207471120. Epub 2023 Mar 16 doi: 10.1073/pnas.2207471120. PMID: 36927155Free PMC Article
Rocatcher A, Desquiret-Dumas V, Charif M, Ferré M, Gohier P, Mirebeau-Prunier D, Verny C, Milea D, Lenaers G; HON Collaborators Group, Bonneau D, Reynier P, Amati-Bonneau P
Brain 2023 Feb 13;146(2):455-460. doi: 10.1093/brain/awac395. PMID: 36317462
Cascavilla ML, Parisi V, Triolo G, Ziccardi L, Borrelli E, Di Renzo A, Balducci N, Lamperti C, Bianchi Marzoli S, Darvizeh F, Sadun AA, Carelli V, Bandello F, Barboni P
Acta Ophthalmol 2018 Mar;96(2):e156-e163. Epub 2017 Sep 19 doi: 10.1111/aos.13557. PMID: 28926202
Newman NJ, Biousse V
Eye (Lond) 2004 Nov;18(11):1144-60. doi: 10.1038/sj.eye.6701591. PMID: 15534600

Diagnosis

Carelli V, La Morgia C, Yu-Wai-Man P
Handb Clin Neurol 2023;194:23-42. doi: 10.1016/B978-0-12-821751-1.00010-5. PMID: 36813316
Ferro Desideri L, Traverso CE, Iester M
Drugs Today (Barc) 2022 Nov;58(11):547-552. doi: 10.1358/dot.2022.58.11.3448291. PMID: 36422516
Rigoli L, Caruso V, Salzano G, Lombardo F
Int J Environ Res Public Health 2022 Mar 9;19(6) doi: 10.3390/ijerph19063225. PMID: 35328914Free PMC Article
Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D
Orphanet J Rare Dis 2012 Jul 9;7:46. doi: 10.1186/1750-1172-7-46. PMID: 22776096Free PMC Article
Kerrison JB, Maumenee IH
Curr Opin Ophthalmol 1997 Dec;8(6):35-40. doi: 10.1097/00055735-199712000-00006. PMID: 10176101

Therapy

Eckmann-Hansen C, Bek T, Sander B, Grønskov K, Larsen M
J Neuroophthalmol 2022 Sep 1;42(3):328-333. Epub 2022 Mar 30 doi: 10.1097/WNO.0000000000001592. PMID: 35439206
Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, Esposito S
J Transl Med 2019 Jul 23;17(1):238. doi: 10.1186/s12967-019-1993-1. PMID: 31337416Free PMC Article
Del Dotto V, Fogazza M, Carelli V, Rugolo M, Zanna C
Biochim Biophys Acta Bioenerg 2018 Apr;1859(4):263-269. Epub 2018 Jan 31 doi: 10.1016/j.bbabio.2018.01.005. PMID: 29382469
Lopez Sanchez MI, Crowston JG, Mackey DA, Trounce IA
Pharmacol Ther 2016 Sep;165:132-52. Epub 2016 Jun 8 doi: 10.1016/j.pharmthera.2016.06.004. PMID: 27288727
O'Neill EC, Danesh-Meyer HV, Kong GX, Hewitt AW, Coote MA, Mackey DA, Crowston JG; Optic Nerve Study Group
Ophthalmology 2011 May;118(5):964-70. Epub 2010 Dec 3 doi: 10.1016/j.ophtha.2010.09.002. PMID: 21126771

Prognosis

Lim HD, Lee SM, Yun YJ, Lee DH, Lee JH, Oh SH, Lee SY
BMC Med Genomics 2023 Apr 11;16(1):79. doi: 10.1186/s12920-023-01506-x. PMID: 37041640Free PMC Article
Ferro Desideri L, Traverso CE, Iester M
Drugs Today (Barc) 2022 Nov;58(11):547-552. doi: 10.1358/dot.2022.58.11.3448291. PMID: 36422516
Rigoli L, Caruso V, Salzano G, Lombardo F
Int J Environ Res Public Health 2022 Mar 9;19(6) doi: 10.3390/ijerph19063225. PMID: 35328914Free PMC Article
Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, Esposito S
J Transl Med 2019 Jul 23;17(1):238. doi: 10.1186/s12967-019-1993-1. PMID: 31337416Free PMC Article
Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D
Orphanet J Rare Dis 2012 Jul 9;7:46. doi: 10.1186/1750-1172-7-46. PMID: 22776096Free PMC Article

Clinical prediction guides

Paprocka J, Jezela-Stanek A, Śmigiel R, Walczak A, Mierzewska H, Kutkowska-Kaźmierczak A, Płoski R, Emich-Widera E, Steinborn B
Genes (Basel) 2023 Apr 25;14(5) doi: 10.3390/genes14050972. PMID: 37239332Free PMC Article
Lim HD, Lee SM, Yun YJ, Lee DH, Lee JH, Oh SH, Lee SY
BMC Med Genomics 2023 Apr 11;16(1):79. doi: 10.1186/s12920-023-01506-x. PMID: 37041640Free PMC Article
Gupta PR, Gospe SM , III
Ophthalmic Genet 2023 Oct;44(5):469-474. Epub 2022 Oct 19 doi: 10.1080/13816810.2022.2135112. PMID: 36262091
Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, Steegborn C, Nowak T, Schutkowski M, Pellegrini L, Sansone L, Villanova L, Runci A, Pucci B, Morgante E, Fini M, Mai A, Russo MA, Tafani M
Autophagy 2015;11(2):253-70. doi: 10.1080/15548627.2015.1009778. PMID: 25700560Free PMC Article
Newman NJ, Biousse V
Eye (Lond) 2004 Nov;18(11):1144-60. doi: 10.1038/sj.eye.6701591. PMID: 15534600

Recent systematic reviews

Dulski J, Souza J, Santos ML, Wszolek ZK
Orphanet J Rare Dis 2023 Jun 22;18(1):160. doi: 10.1186/s13023-023-02772-9. PMID: 37349768Free PMC Article
Lim HD, Lee SM, Yun YJ, Lee DH, Lee JH, Oh SH, Lee SY
BMC Med Genomics 2023 Apr 11;16(1):79. doi: 10.1186/s12920-023-01506-x. PMID: 37041640Free PMC Article
de Muijnck C, Brink JBT, Bergen AA, Boon CJF, van Genderen MM
Surv Ophthalmol 2023 Jul-Aug;68(4):641-654. Epub 2023 Feb 9 doi: 10.1016/j.survophthal.2023.01.012. PMID: 36764396
Harvey JP, Sladen PE, Yu-Wai-Man P, Cheetham ME
J Neuroophthalmol 2022 Mar 1;42(1):35-44. Epub 2021 Sep 30 doi: 10.1097/WNO.0000000000001375. PMID: 34629400
Ham M, Han J, Osann K, Smith M, Kimonis V
Mitochondrion 2019 May;46:262-269. Epub 2018 Aug 27 doi: 10.1016/j.mito.2018.07.006. PMID: 30165240

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