Optic Atrophy
Disease synonyms
Optic atrophy, OPA, Kjer’s Optic Atrophy, Autosomal Dominant Optic Atrophy, ADOA, Dominant Optic Atrophy and Deafness and DOAplus
Inheritance pattern
Autosomal recessive, autosomal dominant, X-linked
Clinical features
Optic atrophy (OPA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing severe visual loss, typically starting during the first decade of life. The disease affects primarily the retinal ganglion neurons and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the deeper brain visual centers. The prevalence of the disease varies from 1/10,000 in Denmark due to a founder effect, to 1/30,000 in the rest of the world 1, 2. Optic atrophy is also known as dominant optic atrophy or Kjer’s Optic Atrophy, named after the Danish ophthalmologist Dr. Poul Kjer who was the first to describe the disease in the Danish population 1, 4.
Optic atrophy is also a feature of mitochondriopathy, as the genes responsible for OPA encode proteins ubiquitously expressed in mitochondria and associated to its inner membrane. Thus, OPA can be not only an isolated ophthalmological and neurological disease, but it can also be syndromic and include extra-ocular symptoms.
The diagnosis of OPA is based on a combination of clinical findings, electrophysiological studies, family history, and molecular genetic testing, and it is diagnosed in individuals with the following:
- Bilateral symmetric vision loss
- Optic nerve paleness (cardinal sign of optic nerve degeneration)
- Visual field defect
- Color vision defect, often described as acquired blue-yellow loss (tritanopia)
- Childhood onset (first decade of life) 3
Electrophysiological recordings showed that visual-evoked responses in affected individuals characteristically demonstrate diminished amplitudes and prolonged latencies 3. Also, the pattern of electroretinogram recordings is abnormal in all patients affected with OPA.
The syndromic form of optic atrophy is accompanied by extra-ophthalmogic findings, including sensorineural hearing loss, ataxia, myopathy, ophtalmophlegia, and others. Mental abnormalities were identified in ~10’% of those affected 4. Syndromic forms of OPA account for up to 20% of all optic atrophies, with extra-ocular signs raging from mild to severe.
Optic atrophy is a clinically and genetically heterogeneous disorder. However, the majority of suspected hereditary optic neuropathy patients (>60%) 5 harbor pathogenic mutations within the OPA1 gene, and ~3% have mutations in the OPA3 gene 8. A broad spectrum of OPA1 pathogenic variants (>370) have been reported to date 5. The OPA1 pathogenic variants are distributed throughout the coding sequence of the gene, but most commonly they are localized in exons 8-16 encoding the GTPase domain of the protein.
Several different pathogenic variants in OPA1 have been reported in individuals with both optic atrophy and hearing loss: p.Arg445His, p.Gly401Asp, p.Leu243Ter, c.983A>G, p.Ile463_Phe464dup, p.Gln437Arg, and p.Ala357LeufsTer4 6.
Furthermore, pathogenic variants causing OPA with cerebellar ataxia, high myopia, spastic paraplegia, or other extra-ocular findings have been reported 7. Autosomal dominant optic atrophy-3 (OPA3), also known as optic atrophy and cataracts, is caused by heterozygous mutations in the OPA3 gene. Optic atrophy type 3 is characterized by classical OPA clinical findings together with the increased urinary excretion of (3-MGC) and 3-methylglutaric acid (3-MGA). Also, methylglutaconic aciduria type III (MGCA3), also known as optic atrophy plus syndrome, is an allelic disorder with similar but more severe features. The mutation c.143-1G>C accounts for 100% of OPA3 pathogenic variants in the Iraqi Jewish population 8. The pathogenic variant c.320_337del, found in an individual of Turkish-Kurdish origin with OPA3-related 3-methylglutaconic aciduria, is the first pathogenic variant found to date in an individual of non-Iraqi Jewish origin 9. The nonsense variant c. 415C>T (p.Gln139Ter), found in the homozygous state in an individual of Indian origin with OPA3-related 3-methylglutaconic aciduria, is the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin 10. Genetic testing for the (most common) OPA3 variants targets the vast majority of OPA3 affected individuals.
Optic nerve degeneration and optic atrophy are present in many disorders in which mitochondrial impairment is the underlying cause for the degeneration of retinal cells. In addition to OPA-genes, mutations in WFS1 and MFN2 cause optic atrophy inherited in an autosomal dominant manner, mutations in AUH, C12orf65, NDUFS1, POLG, SPG7 and TMEM126A are inherited in an autosomal recessive manner, and mutations in TIMM8A are inherited in an X-linked manner. An overview of genes associated with optic atrophy is listed in the table.
Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance |
---|---|---|---|
ABCA4 | 601691 | Macular degeneration, age-related, 2; Stargardt disease type 1; Retinitis pigmentosa 19; Cone-rod dystrophy 3 | AD, AR |
ABCB6 | 605452 | Dyschromatosis universalis hereditaria 3 | AD |
ABHD12 | 613599 | Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract | AR |
ACO2 | 100850 | Infantile cerebellar-retinal degeneration | AR |
ACVR1 | 102576 | Fibrodysplasia ossificans progressiva | AD |
ADAM9 | 602713 | Cone-rod dystrophy 9 | AR |
ADGRV1 | 602851 | Febrile seizures, familial, 4; Usher syndrome type 2C | AD, AR, DiD |
AFG3L2 | 604581 | spinocerebellar ataxia 28; spastic ataxia 5 | AD, AR |
AGK | 610345 | Sengers syndrome; autosomal recessive cataract type 38 | AR |
AHI1 | 608894 | Joubert syndrome 3 | AR |
AIPL1 | 604392 | Leber congenital amaurosis 4 | AD, AR |
ALDH18A1 | 138250 | Cutis laxa, autosomal recessive, type IIIA; Spastic paraplegia 9A, autosomal dominant; spastic paraplegia 9B; Cutis laxa, autosomal dominant 3 | AD, AR |
ALDH1A3 | 600463 | isolated microphthalmia 8 | AR |
AP3B1 | 603401 | Hermansky-Pudlak syndrome type 2 | AR |
APTX | 606350 | Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia | AR |
ARL13B | 608922 | Joubert syndrome 8 | AR |
ARL6 | 608845 | Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 | AR, DiR |
ASB10 | 615054 | Glaucoma 1, open angle, F | |
ATF6 | 605537 | Achromatopsia 7 | AR |
AUH | 600529 | 3-methylglutaconic aciduria, type I | AR |
B9D1 | 614144 | Meckel Syndrome, Type 9 | AR |
B9D2 | 611951 | Meckel syndrome 10 | AR |
BBS1 | 209901 | Bardet-Biedl syndrome type 1 | AR, DiR |
BBS10 | 610148 | Bardet-Biedl syndrome type 10 | AR |
BBS12 | 610683 | Bardet-Biedl syndrome type 12 | AR |
BBS2 | 606151 | Bardet-Biedl syndrome type 2; retinitis pigmentosa type 74 | AR |
BBS4 | 600374 | Bardet-Biedl syndrome 4 | AR |
BBS5 | 603650 | Bardet-Biedl syndrome 5 | AR |
BBS7 | 607590 | Bardet-Biedl syndrome type 7 | AR |
BBS9 | 607968 | Bardet-Biedl syndrome type 9 | AR |
BCOR | 300485 | Microphthalmia, syndromic 2 | XLD |
BEST1 | 607854 | vitelliform macular dystrophy-2; vitreoretinochoroidopathy; Bestrophinopathy, autosomal recessive; Retinitis pigmentosa 50 | AD |
BFSP1 | 603307 | Cataract 33, multiple types | AD, AR |
BFSP2 | 603212 | AD | |
BLOC1S3 | 609762 | Hermansky-Pudlak syndrome 8 | AR |
BLOC1S6 | 604310 | Hermansky-pudlak syndrome 9 | AR |
BMP4 | 112262 | orofacial cleft type 11; Microphthalmia, syndromic 6 | AD |
C12orf65 | 613541 | Combined oxidative phosphorylation deficiency 7 | AR |
C1QTNF5 | 608752 | Retinal degeneration, late-onset, autosomal dominant | AD |
C8orf37 | 614477 | Cone-rod dystrophy 16; Bardet-Biedl syndrome type 21 | AR |
CA4 | 114760 | Retinitis pigmentosa 17 | AD |
CABP4 | 608965 | Night blindness, congenital stationary (incomplete), 2B, autosomal recessive | AR |
CACNA1F | 300110 | Night blindness, congenital stationary (incomplete), 2A, X-linked; Cone-rod dystropy, X-linked, 3; Aland Island eye disease | XL, XLR |
CACNA2D4 | 608171 | Retinal cone dystrophy 4 | AR |
CANT1 | 613165 | Desbuquois dysplasia type 1 | AR |
CC2D2A | 612013 | COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 | AR |
CCDC28B | 610162 | Bardet-Biedl syndrome type 1 | AR, DiR |
CDH23 | 605516 | Usher syndrome type 1D; deafness type 12; susceptibility to pituitary adenomas | AD, AR, DiR |
CDH3 | 114021 | Hypotrichosis, congenital, with juvenile macular dystrophy | AR |
CDHR1 | 609502 | Retinitis pigmentosa 65 | AR |
CEP164 | 614848 | nephronophthisis 15 | AR |
CEP290 | 610142 | Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 | AR |
CEP41 | 610523 | Joubert syndrome 15 | AR |
CERKL | 608381 | Retinitis pigmentosa type 26 | |
CHD7 | 608892 | CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia | AD |
CHM | 300390 | Choroideremia | XLD |
CHMP4B | 610897 | AD | |
CIB2 | 605564 | deafness type 48; Usher syndrome type 1J | AR |
CISD2 | 611507 | Wolfram syndrome 2 | AR |
CLCN7 | 602727 | Osteopetrosis, autosomal dominant 2; Osteopetrosis, autosomal recessive 4 | AD, AR |
CLN3 | 607042 | neuronal ceroid lipofuscinosis type 3 | AR |
CLN5 | 608102 | neuronal ceroid lipofuscinosis type 5 | AR |
CLN6 | 606725 | adulte onset neuronal ceroid lipofuscinosis, Kufs type; neuronal ceroid lipofuscinosis type 6 | AR |
CLN8 | 607837 | neuronal ceroid lipofuscinosis type 8; neuronal ceroid lipofuscinosistype 8, Northern epilepsy variant | AR |
CLPB | 616254 | 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia | AR |
CLRN1 | 606397 | Usher Syndrome type 3A; retinitis pigmentosa type 61 | AR |
CNGA1 | 123825 | Retinitis pigmentosa 49 | |
CNGA3 | 600053 | Achromatopsia type 2 | AR |
CNGB1 | 600724 | Retinitis pigmentosa 45 | AR |
CNGB3 | 605080 | Achromatopsia type 3 | AR |
CNNM4 | 607805 | Jalili syndrome | AR |
COL11A1 | 120280 | Marshall syndrome; Fibrochondrogenesis 1; Stickler syndrome 2 | AD, AR |
COL11A2 | 120290 | Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 | AD, AR |
COL2A1 | 120140 | Epiphyseal dysplasia, multiple, with myopia and deafness; Legg-Calve-Perthes disease; Platyspondylic skeletal dysplasia, Torrance type; Kniest dysplasia; congenital spondyloepiphyseal dysplasia; SMED Strudwick type; Achondrogenesis, type II or hypochondrogenesis; Spondyloperipheral dysplasia; Osteoarthritis with mild chondrodysplasia; Avascular necrosis of the femoral head; Czech dysplasia; Stickler syndrome type 1; Stanescu type spondyloepiphyseal dysplasia | AD |
COL4A1 | 120130 | porencephaly 1; Brain small vessel disease with or without ocular anomalies; Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps; Hemorrhage, intracerebral, susceptibility to | AD |
COL9A1 | 120210 | Stickler syndrome, type IV; Epiphyseal dysplasia, multiple, 6 | AD |
COL9A2 | 120260 | Stickler syndrome, type V | AD, AR |
COL9A3 | 120270 | multiple epiphyseal dysplasia type 3 | AD |
COX7B | 300885 | Linear skin defects with multiple congenital anomalies 2 | XLD |
CPLANE1 | 614571 | oral-facial-digital syndrome 6; Joubert syndrome 17 | AR |
CRB1 | 604210 | pigmented paravenous chorioretinal atrophy; retinitis pigmentosa type 12; Leber congenital amaurosis type 8 | AD, AR |
CRX | 602225 | Cone-rod retinal dystrophy-2; Leber congenital amaurosis 7 | AD |
CRYAA | 123580 | Cataract 9, multiple types | AD, AR |
CRYAB | 123590 | Myopathy, myofibrillar, 2; Cataract 16, multiple types; Myopathy, Myofibrillar, Fatal Infantile Hypertonic, Alpha-B Crystallin-Related; dilated cardiomyopathy-1II | AD, AR |
CRYBA1 | 123610 | AD | |
CRYBA4 | 123631 | Cataract 23 | |
CRYBB1 | 600929 | Cataract 17, multiple types | AD, AR |
CRYBB2 | 123620 | AD | |
CRYBB3 | 123630 | Cataract 22, autosomal recessive | AD, AR |
CRYGB | 123670 | AD | |
CRYGC | 123680 | Cataract 2, multiple types | AD |
CRYGD | 123690 | Cataract 4, multiple types | AD |
CRYGS | 123730 | AD | |
CSPP1 | 611654 | Joubert syndrome 21 | AR |
CTC1 | 613129 | Cerebroretinal microangiopathy with calcifications and cysts | AR |
CTDP1 | 604927 | Congenital cataracts, facial dysmorphism, and neuropathy | AR |
CTNNB1 | 116806 | colorectal cancer; Hepatocellular Carcinoma; Medulloblastoma; Ovarian Cancer; neurodevelopmental disorder with spastic diplegia and visual defects | AD |
CTSD | 116840 | neuronal ceroid lipofuscinosis type 10 | AR |
CYP1B1 | 601771 | primary congenital glaucoma type 3A; anterior segment dysgenesis type 6, multiple subtypes | AR |
CYP27A1 | 606530 | cerebrotendinous xanthomatosis | AR |
DGUOK | 601465 | mitochondrial DNA depletion syndrome 3 | AR |
DHDDS | 608172 | retinitis pigmentosa type 59; Developmental delay and seizures with or without movement abnormalities | AD, AR |
DKC1 | 300126 | X-linked dyskeratosis congenita | XLR |
DNA2 | 601810 | Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant, 6 | AD, AR |
DNAJC19 | 608977 | 3-methylglutaconic aciduria, type 5 | AR |
DNM1L | 603850 | Encephalopahty, lethal, due to defective mitochondrial peroxisomal fission | AD, AR |
DTNBP1 | 607145 | Hermansky-Pudlak syndrome 7 | AR |
EDN3 | 131242 | congenital central hypoventilation syndrome; Waardenburg syndrome type 4B; Hirschsprung disease 4 | AD, AR |
EDNRB | 131244 | Waardenburg syndrome type 4A; Hirschsprung disease, susceptibility to, 2; ABCD syndrome | AD, AR |
EFEMP1 | 601548 | Doyne honeycomb degeneration of retina | AD |
ELOVL4 | 605512 | Spinocerebellar ataxia 34; Stargardt disease 3; Ichthyosis, spastic quadriplegia, and mental retardation | AD, AR |
ENPP1 | 173335 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Arterial calcification, generalized, of infancy, 1; OBESITY; Hypophosphatemic rickets, autosomal recessive, 2; Cole disease | AD, AR |
EPHA2 | 176946 | multiple types cataract type 6 | AD |
ERCC1 | 126380 | Cerebrooculofacioskeletal syndrome 4 | AR |
ERCC2 | 126340 | xeroderma pigmentosum complementation group D; photosensitive trichothiodystrophy type 1; cerebrooculofacioskeletal syndrome type 2 | AR |
ERCC5 | 133530 | xeroderma pigmentosum complementation group G; cerebrooculofacioskeletal syndrome type 3 | AR |
ERCC6 | 609413 | Cockayne syndrome, type B; Lung Cancer; Cerebrooculofacioskeletal syndrome 1 | AD, AR |
EYA1 | 601653 | Branchiootorenal Syndrome 1; Otofaciocervical Syndrome 1; Branchiootic syndrome 1 | AD |
EYS | 612424 | retinitis pigmentosa type 25 | AR |
FAM126A | 610531 | hypomyelinating leukodystrophy-5 | AR |
FAM161A | 613596 | retinitis pigmentosa type 28 | |
FLVCR1 | 609144 | Ataxia, posterior column, with retinitis pigmentosa | AR |
FOXC1 | 601090 | Iridogoniodysgenesis, type 1; Axenfeld-Rieger syndrome, type 3 | AD |
FOXE3 | 601094 | Anterior segment dysgenesis 2, multiple subtypes; Cataract 34, multiple types | AD, AR |
FOXL2 | 605597 | Blepharophimosis, epicanthus inversus, and ptosis | AD, AR |
FRAS1 | 607830 | Fraser syndrome | AR |
FREM1 | 608944 | Manitoba oculotrichoanal syndrome; Bifid nose with or without anorectal and renal anomalies; Trigonocephaly 2 | AD, AR |
FREM2 | 608945 | Fraser syndrome type 2 | AR |
FSCN2 | 607643 | Retinitis pigmentosa 30 | |
FTL | 134790 | Hyperferritinemia With Or Without Cataract; neurodegeneration with brain iron accumulation 3 | AD, AR |
FYCO1 | 607182 | Cataract 18, autosomal recessive | AR |
FZD4 | 604579 | Exudative vitreoretinopathy | AD |
GALE | 606953 | Galactose epimerase deficiency | AR |
GALK1 | 604313 | galactokinase deficiency | AR |
GALT | 606999 | galactosemia | AR |
GBA | 606463 | Lewy body dementia; Susceptibility to late-onset Parkinson disease; Gaucher disease type 1; Gaucher disease type 2 (acute); Gaucher disease type 3 (subacute/ chronic); Gaucher disease, cardiovascular form; Gaucher disease, perinatal-lethal form | AD, AR |
GCNT2 | 600429 | Cataract 13 with adult i phenotype | AD, AR |
GDF3 | 606522 | Klippel-Feil syndrome 3, autosomal dominant; Microphthalmia with coloboma 6; isolated microphthalmia 7 | AD |
GDF6 | 601147 | Klippel-feil syndrome 1, autosomal dominant; isolated microphthalmia 4; Microphthalmia with coloboma 6; Leber congenital amaurosis 17 | AD, AR |
GJA1 | 121014 | Oculodentodigital dysplasia | AD, AR |
GJA3 | 121015 | Cataract 14, multiple types | AD |
GJA8 | 600897 | Cataract 1, multiple types | AD |
GNAT2 | 139340 | Acromatopsia | |
GNPTG | 607838 | mucolipidosis III gamma | AR |
GPR143 | 300808 | Albinism, Ocular, Type I; Nystagmus 6, congenital, X-linked | XL, XLR |
GRIP1 | 604597 | AR | |
GRN | 138945 | frontotemporal lobar degeneration with ubiquitin-positive inclusions; neuronal ceroid lipofuscinosis type 11 | AD, AR |
GUCA1A | 600364 | Cone-rod dystrophy 14 | AD |
GUCA1B | 602275 | Retinitis pigmentosa 48 | |
GUCY2D | 600179 | Leber congenital amaurosis type 1; cone-rod dystrophy type 6 | AD, AR |
HCCS | 300056 | Microphthalmia, syndromic 7 | XLD |
HESX1 | 601802 | Septooptic dysplasia | AD, AR |
HEXA | 606869 | Tay-Sachs disease/ GM2-gangliosidosis | AR |
HGSNAT | 610453 | mucopolysaccharidosis type IIIC; retinitis pigmentosa type 73 | AR |
HK1 | 142600 | Hemolytic anemia due to hexokinase deficiency; Neuropathy, hereditary motor and sensory, Russe type; Retinitis pigmentosa 79; Neurodevelopmental disorder with visual defects and brain anomalies | AD, AR |
HMX1 | 142992 | AR | |
HPS1 | 604982 | Hermansky-Pudlak syndrome type 1 | AR |
HPS3 | 606118 | Hermansky-Pudlak syndrome type 3 | AR |
HPS4 | 606682 | Hermansky-Pudlak syndrome type 4 | AR |
HPS5 | 607521 | Hermansky-Pudlak syndrome type 5 | AR |
HPS6 | 607522 | Hermansky-Pudlak syndrome type 6 | AR |
HSF4 | 602438 | Cataract 5, multiple types | AD |
HTRA2 | 606441 | Parkinson disease 13; 3-methylglutaconic aciduria, type VIII | AR |
IDH3B | 604526 | Retinitis pigmentosa 46 | |
IFT140 | 614620 | Mainzer-Saldino syndrome; retinitis pigmentosa type 80 | AR |
IFT172 | 607386 | Short-rib thoracic dysplasia 10 with or without polydactyly | AR |
IFT27 | 615870 | Bardet-Biedl syndrome 19 | AR |
IMPDH1 | 146690 | Retinitis pigmentosa 10; Leber congenital amaurosis 11 | AD |
IMPG2 | 607056 | Retinitis pigmentosa 56; vitelliform macular dystrophy-5 | AD, AR |
INPP5E | 613037 | Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis | AR |
IQCB1 | 609237 | Senior-Loken syndrome 5 | AR |
KCNJ13 | 603208 | AD, AR | |
KCNV2 | 607604 | Retinal cone dystrophy 3B | AR |
KIF11 | 148760 | Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation | AD |
KIF7 | 611254 | Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 | AR |
KIT | 164920 | Mast cell disease; Piebaldism; Spermatocytic seminoma, somatic; acute myeloid leukemia; gastrointestinal stromal tumor | AD |
KLHL7 | 611119 | Retinitis pigmentosa 42; Cold-induced sweating syndrome 3 | AD, AR |
LCA5 | 611408 | Leber congenital amaurosis type 5 | AR |
LEMD2 | 616312 | AR | |
LEP | 164160 | Leptin deficiency | AR |
LEPR | 601007 | Morbid obesity due to leptin receptor deficiency | AR |
LIM2 | 154045 | Cataract 19 | AR |
LMX1B | 602575 | Nail-patella syndrome | AD |
LOXL1 | 153456 | Exfoliation syndrome | AD |
LRAT | 604863 | Leber congenital amaurosis 14 | AR |
LRMDA | 614537 | Albinism, oculocutaneous, type VII | AR |
LRP2 | 600073 | Donnai-Barrow syndrome | AR |
LRP5 | 603506 | Hyperostosis Corticalis Generalisata, Benign Form Of Worth, With Torus Palatinus; OSTEOPOROSIS; Osteoporosis-pseudoglioma syndrome; Exudative vitreoretinopathy 4; Bone Mineral Density Quantitative Trait Locus 1; autosomal dominant osteopetrosis type 1; van Buchem disease, type 2 | AD, AR |
LSS | 600909 | cataract 44 | AR |
LTBP2 | 602091 | Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma; Glaucoma 3, primary congenital, D; Weill-Marchesani Syndrome 3 | AR |
LYST | 606897 | Chediak-Higashi syndrome | AR |
LZTFL1 | 606568 | Bardet-Biedl syndrome 17 | AR |
MAB21L2 | 604357 | Microphthalmia, syndromic 14 | AD, AR |
MAF | 177075 | Ayme-Gripp syndrome; Cataract, pulverulent or cerulean, with or without microcornea | AD |
MAK | 154235 | Retinitis pigmentosa 62 | AR |
MC1R | 155555 | oculocutaneous albinism type 2; skin/hair/eye pigmentation 2; Melanoma, cutaneous malignant, susceptibility to, 5 | AR |
MERTK | 604705 | Retinitis pigmentosa 38 | AR |
MFN2 | 608507 | hereditary motor and sensory neuropathy type VIA with optic atrophy; axonal Charcot-Marie-Tooth disease type 2A2A; axonal Charcot-Marie-Tooth disease type 2A2B | AD, AR |
MFRP | 606227 | Nanophthalmos 2; isolated microphthalmia 5 | AR |
MFSD8 | 611124 | neuronal ceroid lipofuscinosis type 7; macular dystrophy with central cone involvement | AR |
MIP | 154050 | AD | |
MITF | 156845 | Albinism, Ocular, With Sensorineural Deafness; Tietz Syndrome; Waardenburg syndrome type 2A; Melanoma, Cutaneous Malignant, Susceptibility To, 8 | AD, AR |
MKKS | 604896 | McKusick-Kaufman syndrome; Bardet-Biedl syndrome type 6 | AR |
MKS1 | 609883 | Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 | AR |
MLPH | 606526 | Griscelli syndrome, type 3 | AR |
MYH9 | 160775 | Fechtner syndrome; Macrothrombocytopenia and progressive sensorineural deafness; May-Hegglin anomaly; Sebastian syndrome; deafness type 17 | AD |
MYO5A | 160777 | Griscelli syndrome, type 1 | AR |
MYO7A | 276903 | Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 | AD, AR |
MYOC | 601652 | Glaucoma 1, Open Angle, A | AD |
NAA10 | 300013 | Ogden syndrome; Microphthalmia, syndromic 1 | XL, XLD, XLR |
NDP | 300658 | Exudative Vitreoretinopathy 2, X-Linked; Norrie disease | XLD, XLR |
NF2 | 607379 | neurofibromatosis type 2; Schwannomatosis; Meningioma, familial, susceptibility to | AD |
NHS | 300457 | Nance-Horan syndrome | XL, XLD |
NMNAT1 | 608700 | Leber congenital amaurosis 9 | AR |
NPHP1 | 607100 | nephronophthisis 1; Joubert syndrome 4 | AR |
NPHP3 | 608002 | Renal-hepatic-pancreatic dysplasia 1; Meckel syndrome 7; nephronophthisis 3 | AR |
NPHP4 | 607215 | nephronophthisis 4 | AR |
NR0B2 | 604630 | OBESITY | AD, AR |
NR2F1 | 132890 | Bosch-Boonstra-Schaaf optic atrophy syndrome | AD |
NRL | 162080 | Retinitis pigmentosa 27 | AD |
NTF4 | 162662 | Glaucoma 1, open angle, 1O | |
OCA2 | 611409 | oculocutaneous albinism type 2 | AR |
OCRL | 300535 | Dent disease type 2; Lowe oculocerebrorenal syndrome | XLR |
OFD1 | 300170 | Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 | XLD, XLR |
OPA1 | 605290 | Optic atrophy plus syndrome; optic atrophy type 1; Behr syndrome; Glaucoma, normal tension, susceptibility to; Mitochondrial DNA depletion syndrome 14 | AD, AR |
OPA3 | 606580 | Optic atrophy type 3 with cataract; 3-methylglutaconic aciduria type III | AD, AR |
OPN1LW | 300822 | Blue cone monochromacy | XL, XLR |
OPN1MW | 300821 | Blue cone monochromacy | XL, XLR |
OPTN | 602432 | Adult-onset primary open angle glaucoma; Glaucoma, normal tension, susceptibility to; amyotrophic lateral sclerosis 12 | AD |
OSTM1 | 607649 | Osteopetrosis, autosomal recessive 5 | AR |
OTX2 | 600037 | Microphthalmia, syndromic 5; Pituitary hormone deficiency, combined, 6 | AD |
P3H2 | 610341 | AR | |
PAX2 | 167409 | Papillorenal syndrome | AD |
PAX3 | 606597 | Waardenburg syndrome, type 3; Waardenburg syndrome type 1 | AD, AR |
PAX6 | 607108 | Aniridia 1; foveal hypoplasia type 1 | AD |
PCARE | 613425 | Retinitis pigmentosa 54 | |
PCDH15 | 605514 | Usher syndrome type 1D; Usher syndrome type 1F; deafness type 23 | AR, DiR |
PDE6A | 180071 | Retinitis pigmentosa 43 | |
PDE6B | 180072 | Night blindness, congenital stationary, autosomal dominant 2; Retinitis pigmentosa 40 | AD, AR |
PDE6C | 600827 | Cone dystrophy 4 | AR |
PDE6G | 180073 | Retinitis pigmentosa 57 | AR |
PDE6H | 601190 | Retinal cone dystrophy 3 | AD, AR |
PDZD7 | 612971 | Usher syndrome type 2A; Usher syndrome type 2C; Deafness, autosomal recessive 57 | AR, DiD |
PEX1 | 602136 | Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B | AR |
PEX2 | 170993 | peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B | AR |
PEX7 | 601757 | Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) | AR |
PHF6 | 300414 | Borjeson-Forssman-Lehmann syndrome | XLR |
PHYH | 602026 | Refsum disease | AR |
PIK3R5 | 611317 | Ataxia-oculomotor apraxia 3 | AR |
PITPNM3 | 608921 | Cone-rod dystrophy 5 | AD |
PITX2 | 601542 | Axenfeld-Rieger syndrome, type 1 | AD |
PITX3 | 602669 | Anterior segment mesenchymal dysgenesis; Cataract 11, multiple types | AD, AR |
PLA2G5 | 601192 | AR | |
PNKP | 605610 | type 2B2 Charcot-Marie-Tooth disease; early infantile epileptic encephalopathy 10 | AR |
PNPLA6 | 603197 | Boucher-Neuhauser syndrome; spastic paraplegia 39 | AR |
POLG | 174763 | progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B | AD, AR |
POLG2 | 604983 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 | AD, AR |
POMC | 176830 | OBESITY; Proopiomelanocortin Deficiency | AD, AR |
POMGNT1 | 606822 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A3; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B3; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C3; retinitis pigmentosa type 76 | AR |
PPARG | 601487 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 | AD, AR |
PPT1 | 600722 | neuronal ceroid lipofuscinosis type 1 | AR |
PQBP1 | 300463 | Renpenning Syndrome 1 | XLR |
PRCD | 610598 | Retinitis pigmentosa 36 | |
PRKCG | 176980 | spinocerebellar ataxia 14 | AD |
PROM1 | 604365 | Stargardt disease 4; Macular dystrophy, retinal, 2; Retinitis pigmentosa 41; Cone-rod dystrophy 12 | AD, AR |
PRPF3 | 607301 | Retinitis pigmentosa 18 | AD |
PRPF31 | 606419 | Retinitis pigmentosa 11 | AD |
PRPF6 | 613979 | Retinitis pigmentosa 60 | AD |
PRPF8 | 607300 | Retinitis pigmentosa 13 | AD |
PRPH2 | 179605 | Retinitis punctata albescens; Patterned dystrophy of retinal pigment epithelium (macular dystrophy); Retinitis pigmentosa 7; vitelliform macular dystrophy-3; Choriodal dystrophy, central areolar 2 | AD, AR |
PRPS1 | 311850 | Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth | XL, XLR |
PRSS56 | 613858 | isolated microphthalmia 6 | AR |
RAB18 | 602207 | Warburg micro syndrome 3 | AR |
RAB27A | 603868 | Griscelli syndrome, type 2 | AR |
RAB3GAP1 | 602536 | Warburg micro syndrome 1 | AR |
RAB3GAP2 | 609275 | Martsolf syndrome; Warburg micro syndrome 2 | AR |
RARB | 180220 | syndromic microphthalmia, type 12 | AD, AR |
RAX | 601881 | isolated microphthalmia 3 | AR |
RAX2 | 610362 | Cone-rod dystrophy 11; Macular degeneration, age-related, 6 | AD |
RBP3 | 180290 | Retinitis pigmentosa 66 | AR |
RBP4 | 180250 | Retinal dystrophy, iris coloboma, and comedogenic acne syndrome | AD, AR |
RD3 | 180040 | Leber congenital amaurosis 12 | AR |
RDH12 | 608830 | Leber congenital amaurosis type 13 | AD, AR |
RDH5 | 601617 | Retinitis punctata albescens | AD, AR |
RGR | 600342 | Retinitis pigmentosa 44 | |
RGS9 | 604067 | Bradyopsia | |
RGS9BP | 607814 | Bradyopsia | |
RHO | 180380 | Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1; Retinitis Pigmentosa 4 | AD, AR |
RIMS1 | 606629 | Cone-rod dystrophy 7 | |
RLBP1 | 180090 | Retinitis punctata albescens | AD, AR |
ROM1 | 180721 | Retinitis pigmentosa 7 | AD, AR |
RP1 | 603937 | Retinitis pigmentosa 1 | AD, AR |
RP1L1 | 608581 | occult macular dystrophy | AD, AR |
RP2 | 300757 | Retinitis pigmentosa 2 | XL |
RPE65 | 180069 | Leber congenital amaurosis type 2; retinitis pigmentosa type 20 | AD, AR |
RPGR | 312610 | Retinitis pigmentosa 3; Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness; Macular degeneration, X-linked atrophic; Cone-rod dystrophy, X-linked, 1 | XL, XLR |
RPGRIP1 | 605446 | Cone-rod dystrophy 13; Leber congenital amaurosis 6 | AR |
RPGRIP1L | 610937 | COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 | AR |
RRM2B | 604712 | mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 | AD, AR |
RS1 | 300839 | Retinoschisis | XLR |
RTN4IP1 | 610502 | Optic atrophy 10 with or without ataxia, mental retardation, and seizures | AR |
SAG | 181031 | NIGHT BLINDNESS, CONGENITAL STATIONARY, OGUCHI TYPE 1; Retinitis pigmentosa 47 | AR |
SBF2 | 607697 | type 4B2 Charcot-Marie-Tooth disease | AR |
SDCCAG8 | 613524 | Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 | AR |
SEMA4A | 607292 | Retinitis pigmentosa 35; Cone-rod dystrophy 10 | AD, AR |
SERAC1 | 614725 | 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome). | AR |
SETX | 608465 | amyotrophic lateral sclerosis 4; autosomal recessive spinocerebellar ataxia 1 | AD, AR |
SHH | 600725 | Holoprosencephaly 3; Solitary Median Maxillary Central Incisor; Schizencephaly; Microphthalmia, Isolated, With Coloboma 5 | AD |
SIL1 | 608005 | Marinesco-Sjogren syndrome | AR |
SIX3 | 603714 | Holoprosencephaly 2; Schizencephaly | AD |
SIX6 | 606326 | Microphthalmia with cataract 2 | AR |
SLC16A12 | 611910 | AD | |
SLC24A5 | 609802 | Oculocutaneous albinism-6 | AR |
SLC25A4 | 103220 | Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant, 2; mitochondrial DNA depletion syndrome 12; mitochondrial DNA depletion syndrome type 12A | AD, AR |
SLC25A46 | 610826 | Neuropathy, hereditary motor and sensory, type VIB | AR |
SLC33A1 | 603690 | spastic paraplegia 42; Congenital cataracts, hearing loss, and neurodegeneration | AD, AR |
SLC45A2 | 606202 | Oculocutaneous albinism, type IV | AR |
SLC9A6 | 300231 | Christianson type of X-linked syndromic mental retardation | XLD |
SMCHD1 | 614982 | Fascioscapulohumeral muscular dystrophy 2, digenic | AD |
SMOC1 | 608488 | AR | |
SNAI2 | 602150 | Piebaldism; Waardenburg syndrome type 2d | AD, AR |
SNRNP200 | 601664 | Retinitis pigmentosa 33 | AD |
SNX10 | 614780 | Osteopetrosis, autosomal recessive 8 | AR |
SOX10 | 602229 | PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C | AD |
SOX2 | 184429 | Microphthalmia, Syndromic 3 | AD |
SPATA7 | 609868 | Leber congenital amaurosis 3 | |
SPG7 | 602783 | spastic paraplegia 7 | AD, AR |
STRA6 | 610745 | Microphthalmia, isolated, with coloboma 8 | AR |
TBC1D20 | 611663 | Warburg micro syndrome 4 | AR |
TBK1 | 604834 | Frontotemporal dementia and/or amyotrophic lateral sclerosis type 4; Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 | AD |
TCIRG1 | 604592 | osteopetrosis type 1 | AR |
TCTN1 | 609863 | Joubert syndrome 13 | AR |
TCTN2 | 613846 | Meckel syndrome 8; Joubert syndrome type 24 | AR |
TCTN3 | 613847 | oral-facial-digital syndrome 4; Joubert syndrome 18 | AR |
TDRD7 | 611258 | Cataract type 36 | AR |
TENM3 | 610083 | microphthalmia with coloboma 9 | AR |
TFAP2A | 107580 | Branchiooculofacial syndrome | AD |
TIMM8A | 300356 | Mohr-Tranebjaerg syndrome | XLR |
TIMP3 | 188826 | Sorsby fundus dystrophy | AD |
TK2 | 188250 | mitochondrial DNA depletion syndrome 2 | AR |
TMEM126A | 612988 | Optic Atrophy 7 | AR |
TMEM138 | 614459 | Joubert syndrome 16 | AR |
TMEM216 | 613277 | Meckel Syndrome type 2; Joubert syndrome type 2 | AR |
TMEM231 | 614949 | Joubert syndrome 20; Meckel syndrome, type 11 | AR |
TMEM237 | 614423 | Joubert syndrome 14 | AR |
TMEM67 | 609884 | COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 | AR |
TMEM70 | 612418 | Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 | AR |
TNFRSF11A | 603499 | familial expansile osteolysis; Osteopetrosis, autosomal recessive 7 | AD, AR |
TNFSF11 | 602642 | autosomal recessive osteopetrosis type 2 | AR |
TOPORS | 609507 | Retinitis pigmentosa 31 | |
TPP1 | 607998 | neuronal ceroid lipofuscinosis type 2; autosomal recessive spinocerebellar ataxia type 7 | AR |
TRIM32 | 602290 | limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 | AR |
TRNT1 | 612907 | Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay | AR |
TSPAN12 | 613138 | Exudative vitreoretinopathy 5 | AD |
TTC21B | 612014 | Short-rib thoracic dysplasia 4 with or without polydactyly; nephronophthisis 12 | AD, AR |
TTC8 | 608132 | retinitis pigmentosa type 51; Bardet-Biedl syndrome type 8 | AR |
TTPA | 600415 | ataxia with vitamin E deficiency | AR |
TULP1 | 602280 | Retinitis pigmentosa 14 | AR |
TWNK | 606075 | Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 | AD, AR |
TYMP | 131222 | mitochondrial DNA depletion syndrome 1 | AR |
TYR | 606933 | Albinism, Ocular, With Sensorineural Deafness; oculocutaneous albinism type 1A; Skin/hair/eye pigmentation 3; Albinism, oculocutaneous, type IB | AD, AR |
TYRP1 | 115501 | Albinism, oculocutaneous, type III | AR |
UNC45B | 611220 | Cataract type 43 | AD |
USH1C | 605242 | Usher syndrome type IC; deafness type 18A | AR |
USH1G | 607696 | Usher syndrome type 1G | AR |
USH2A | 608400 | Usher syndrome type 2A; retinitis pigmentosa type 39 | AR |
VCAN | 118661 | Wagner syndrome 1 | AD |
VIM | 193060 | AD | |
VPS13B | 607817 | Cohen syndrome | AR |
VSX2 | 142993 | microphthalmia with coloboma 3; isolated microphthalmia 2 | |
WDPCP | 613580 | Bardet-Biedl syndrome 15 | AR |
WDR19 | 608151 | Short-rib thoracic dysplasia 5 with or without polydactyly; nephronophthisis 13; Cranioectodermal dysplasia 4; Senior-Loken syndrome 8 | AR |
WDR36 | 609669 | Glaucoma 1, open angle, G | |
WFS1 | 606201 | congenital nuclear cataract type 41; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome | AD, AR |
WHRN | 607928 | deafness type 31; Usher syndrome type 2D | AR |
ZIC2 | 603073 | Holoprosencephaly 5 | AD |
ZNF423 | 604557 | nephronophthisis 14; Joubert syndrome 19 | AD, AR |
ZNF513 | 613598 | Retinitis pigmentosa 58 | AR |
To date, there is no preventative or curative treatment for optic atrophy. However, symptomatic treatment that is initiated before the development of optic atrophy can be helpful in saving useful vision. The role of intravenous steroids was proven as helpful in cases with optic neuritis. Early diagnosis and prompt treatment can help patients with progressive and severe neuropathies. Development of therapeutic approaches based on stem cell therapy and gene therapy are in progress.
CENTOGENE offers sequencing and deletion/duplication analysis for the Optic atrophy panel (genes: ACO2, AFG3L2, C12ORF65, CISD2, MFN2, NR2F1, OPA1, OPA3, RTN4IP1, SLC25A46, SPG7, TIMM8A, TMEM126A, WFS1).
Differential diagnosis
The differential diagnosis of optic atrophy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Leber hereditary optic neuropathy, caused by mutations in mtDNA (most commonly: m.11778G>A, m.14484T>C, m.3460G>A)
- Wolfram´s syndrome, caused by mutations in WF1 or CISD2
- Friedreich ataxia, caused by mutations in the FXN gene
- Deafness-dystonia-optic neuronopathy syndrome, caused by mutations in the TIMM8A gene
- Inborn errors of metabolism with 3-methylglutaconic aciduria
- Acquired optic neuropathy caused by nutritional deficiencies, toxic exposures or certain medications.
Testing strategy
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology.This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for optic atrophy using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Optic atrophy panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the optic atrophy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
Referral reasons
The following individuals are candidates for optic atrophy testing:
- Individuals with a family history of optic atrophy and presentation of the most common symptoms
- Individuals without a positive family history of optic atrophy, but with symptoms resembling the disease
- Individuals with a negative but suspected family history of optic atrophy, in order to perform proper genetic counseling.
Test utility
Sequencing, deletion/duplication of the optic atrophy panel genes should be performed in all individuals suspected of having Maple syrup urine disease and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the optic atrophy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.