Alternative titles; symbols
SNOMEDCT: 717336005; ORPHA: 98673; DO: 0111441;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q29 | Optic atrophy 1 | 165500 | Autosomal dominant | 3 | OPA1 | 605290 |
A number sign (#) is used with this entry because optic atrophy-1 (OPA1) is caused by heterozygous mutation in the gene encoding the human homolog of the S. pombe dynamin-related protein Msp1 (OPA1; 605290) on chromosome 3q29.
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.
Iverson (1958) reported congenital optic atrophy in 3 generations. The clear autosomal dominant pattern of inheritance and congenital nature distinguished it from Leber hereditary optic atrophy (LHON; 535000).
Caldwell et al. (1971) described 2 families with insidious onset of optic atrophy in childhood. There were no neurologic, congenital, or developmental abnormalities. Caldwell et al. (1971) classified the familial optic atrophies into 6 groups: congenital dominant, congenital recessive, juvenile dominant, juvenile recessive, Leber, and autosomal recessive Behr syndrome (210000). The features of the 6 groups were usefully compared. Snell (1897) is generally credited with first describing a form of optic atrophy separate from Leber optic atrophy. Stendahl-Brodin et al. (1978) described a family with probable autosomal dominant inheritance of late-onset optic atrophy. Linkage to HLA was suggested. Johnston et al. (1979) studied an extensively affected kindred and had an opportunity for histologic examination of the eyes of an affected 56-year-old woman. Her vision had been severely reduced since childhood. Pathologic changes were diffuse atrophy of the ganglion cell layer of the retina and loss of myelin and nerve tissue within the optic nerve. They suggested that the disorder is a primary degeneration of retinal ganglion cells. Most affected members of the family had severe unclassified color defects.
Eiberg et al. (1994) described autosomal dominant optic atrophy as being characterized by an insidious onset of optic atrophy in early childhood with moderate to severe decrease of visual acuity, blue-yellow dyschromatopsia, and centrocecal scotoma of varying density. Many affected members of the families may be unaware of having the disease or of its hereditary aspects.
Votruba et al. (1998) evaluated the clinical features in 21 families with 3q-linked dominant optic atrophy. They found wide intra- and interfamilial phenotypic variation, with visual function deteriorating with age in only some families. There was evidence of degeneration of the ganglion cell layer, predominantly from central retina, but this was not the exclusive result of either parvocellular or magnocellular cell loss.
Johnston et al. (1999) refined the clinical diagnostic criteria for dominant optic atrophy on the basis of linkage studies, i.e., the study of subjects who had been classified clinically as definitely or possibly affected on the basis of a domiciliary examination before genetic analysis, and the comparison of these results with the haplotype analysis. Clinically, 43 subjects were identified as definitely affected, 4 as possibly affected, and 45 as unaffected. Visual acuity in affected subjects ranged from 6/6 to count fingers and declined with age. On genetic analysis, a specific haplotype was identified in each family, which was found in all definitely affected members but not in those regarded as unaffected. The 4 possibly affected individuals also bore the haplotype that segregated with the disorder. Contrary to accepted criteria, symptoms began before the age of 10 years in only 58% of affected individuals. Visual acuity in affected subjects was highly variable. A mild degree of temporal or diffuse pallor of the optic disc and minimal color vision defects, in the context of the family with dominant optic atrophy, were highly suggestive of an individual being affected, even if visual acuity was normal.
In 2 large U.S. midwestern families with autosomal dominant optic atrophy, Chen et al. (2000) showed linkage to 3q28-q29 and pointed out considerable intrafamilial phenotypic variation as well as sex-influenced severity. Visual loss among affected males was more severe than among affected females.
Fournier et al. (2001) examined optic disc morphology in patients with dominant optic atrophy to elucidate features that would distinguish dominant optic atrophy from normal tension glaucoma (606657). The optic atrophy patients had a mild to moderate reduction in visual acuity and color vision. Seventy-eight percent had a temporal wedge-shaped area of optic disc excavation. All involved eyes had moderate to severe pallor of the temporal neuroretinal rim, with milder pallor of the remaining noncupped rim. All eyes had a slate-gray crescent within the neuroretinal rim tissue and some degree of peripapillary atrophy. The authors concluded that several clinical features, including early age of onset, preferential loss of central vision, sparing of the peripheral fields, pallor of the remaining neuroretinal rim, and a family history of unexplained visual loss or optic atrophy, help distinguish patients with dominant optic atrophy from those with normal tension glaucoma.
To analyze the influence of OPA1 gene mutations on optic nerve head morphology in patients with dominant optic atrophy, Barboni et al. (2010) studied the optic nerve head of 28 OPA1 mutation-positive patients from 11 pedigrees and 56 age-matched controls by optical coherence tomography (OCT). Patients showed a significantly smaller optic disc area (P less than 0.0001), and vertical (P = 0.018), and horizontal (P less than 0.0001) disc diameters, compared with controls. Stratification of the results for the single OPA1 mutation revealed normal optic nerve head area with 2 mutations, whereas a missense mutation linked to a 'dominant optic atrophy plus' phenotype (605290.0017) had the smallest ONH measurements. Barboni et al. (2010) concluded that their observations suggested a theretofore unrecognized role for OPA1 in eye development, and in particular in modeling optic nerve head size and conformation.
Using optical coherence tomography (OCT), Barboni et al. (2011) compared the retinal nerve fiber layers (RNFLs) of 33 dominant optic atrophy patients with those of 43 healthy control subjects matched for age and optic nerve head size. They found that patients had significant RNFL thickness reduction in all quadrants, with a preferential involvement of the temporal and inferior sectors. The progressive decline in RNFL thickness with age was similar to that observed in healthy subjects and was more evident in the 2 quadrants with higher residual amounts of fibers, i.e., the superior and inferior quadrants. The temporal quadrant was profoundly depleted of fiber so that the further rate of loss of microns per year was close to zero, whereas the nasal quadrant was spared the most by neurodegeneration. Barboni et al. (2011) concluded that these findings, together with their description of small optic nerve head size in dominant optic atrophy (Barboni et al., 2010), strongly suggested that patients with this disease are born with fewer optic nerve axons and supported the hypothesis that subsequent visual loss depends on further age-related loss of fibers, which also occurred in controls.
The transmission pattern of OPA1 in the families reported by Cohn et al. (2007) was consistent with autosomal dominant inheritance.
The pathogenic characteristics of OPA1 resemble those of Leber hereditary optic neuropathy (535000), which results from a defect of the mitochondrion. Mutations in the mitochondrial gene responsible presumably lead to insufficient energy supply in the highly energy-demanding neurons of the optic nerve, notably the papillomacular bundle, and cause blindness by a compromise of axonal transport in retinal ganglion cells. Alexander et al. (2000) hypothesized that mutations in the OPA1 gene affect mitochondrial integrity, resulting in an impairment of energy supply.
Using phosphorus magnetic resonance spectroscopy, Lodi et al. (2004) demonstrated defective oxidative phosphorylation in 6 OPA1 patients from 2 unrelated families with a 4-bp deletion in the OPA1 gene (605290.0003). The time constant of postexercise phosphocreatine resynthesis was significantly increased in patients compared to controls, indicating a reduced rate of mitochondrial ATP production in the patients. Lodi et al. (2004) noted that similar findings had been observed in patients with LHON. Lodi et al. (2011) performed similar studies as Lodi et al. (2004) 18 patients, including 6 previously reported by Lodi et al. (2004), with genetically confirmed OPA1 due to different mutations. Sixteen patients carried truncating mutations resulting in haploinsufficiency, and 2 patients had missense mutations. Calf muscles from patients showed reduced phosphorylation potential in patients at rest, indicating reduced energy reserve, although only 4 patients had levels below the normal range. Patients showed shorter exercise duration compared to controls, indicating reduced oxidative capacity. Postexercise skeletal muscle Vmax of mitochondrial ATP synthesis was reduced by 36% in patients compared to controls, and only 2 patients had normal Vmax levels. Four of 10 patients had increased serum lactate after exercise. Despite these defects, muscle biopsies available from 5 patients did not show clear-cut hallmarks of mitochondrial myopathy, such as ragged-red fibers, and there was not clear evidence of mtDNA deletions.
Payne et al. (2004) hypothesized that although OPA1 is a nuclear gene, the fact that the gene product localizes to mitochondria suggests that mitochondrial dysfunction might be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia.
Using quantitative real-time PCR, Kim et al. (2005) found significantly decreased levels of cellular mtDNA in blood from 4 of 8 patients with OPA1 (range, 412.0 to 648.0 copies per cell) compared to controls (1,148.6 +/- 406.9). Three patients had decreased levels (813.2 to 1,133.6), and 1 patient had normal levels (1,455.3). The findings were consistent with the hypothesis that OPA1 gene mutations result in decreased numbers of mitochondrial organelles via apoptosis. However, neither mtDNA content nor genotype correlated with phenotype, indicating that additional epigenetic factors are involved. Kim et al. (2005) postulated that selective damage to retinal ganglion cells in OPA1 may result from a combination of high energy requirements of retinal cells in the macular area and increased sensitivity of retinal ganglial cells to free radicals and oxidative stress.
Amati-Bonneau et al. (2005) found fragmentation of the mitochondrial network and defects in oxidative phosphorylation in skin fibroblasts from patients with optic atrophy and deafness.
In fibroblasts derived from 16 patients with hereditary optic neuropathy, including either LHON, OPA1, or OPA3, Chevrollier et al. (2008) found a common coupling defect of oxidative phosphorylation, resulting in reduced efficiency of ATP synthesis. LHON fibroblasts showed a mean decrease of 39% in complex I activity compared to controls. OPA1 and OPA3 fibroblasts showed normal complex I activities, but a mean decrease of 25% in complex IV activity and a mean 60% increase in complex V activity. Resting respiration was about twice as high in all LHON, OPA1, and OPA3 fibroblasts compared to controls, reflecting a proton leak or electron slip. However, all mutant cell lines used a greater proportion of routine respiratory capacity during routine compared to controls, suggesting a compensatory mechanism. The energy defect was most pronounced in fibroblasts from patients with additional neurologic symptoms.
Yu-Wai-Man et al. (2010) investigated the mtDNA changes induced by OPA1 mutations in skeletal muscle biopsies from 15 patients with both isolated DOA and neuromuscularly impaired (DOA+; 125250) phenotypes. There was a 2- to 4-fold increase in mtDNA copy number at the single-fiber level, and patients with DOA+ features had significantly greater mtDNA proliferation in their cytochrome c oxidase (COX; see 516030)-negative skeletal muscle fibers compared to patients with isolated optic neuropathy. Low levels of wildtype mtDNA molecules were present in COX-deficient muscle fibers from both isolated DOA and DOA+ patients, implicating haploinsufficiency as the mechanism responsible for the biochemical defect. The authors proposed a 'maintenance of wildtype' hypothesis, with secondary mtDNA deletions induced by OPA1 mutations triggering a compensatory mitochondrial proliferative response in order to maintain an optimal level of wildtype mtDNA genomes. However, when deletion levels reach a critical level, further mitochondrial proliferation may lead to replication of the mutant species at the expense of wildtype mtDNA, resulting in the loss of respiratory chain COX activity.
Ban et al. (2010) showed that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids, such as cardiolipin. Lipid association triggered assembly of OPA1 into higher order oligomers. In addition, OPA1 could promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies were observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 was suppressed by GTP-gamma-S. OPA1 disease alleles associated with dominant optic atrophy displayed selective defects in several activities, including cardiolipin association, GTP hydrolysis, and membrane tubulation. Ban et al. (2010) concluded that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis, and lead to membrane deformation into tubules.
In a population-based epidemiologic study of autosomal dominant optic atrophy in the north of England, Yu-Wai-Man et al. (2010) determined that the minimum point prevalence was 2.87 per 100,000, or approximately 1 in 35,000. The point prevalence was 2.09 per 100,000 when only OPA1-positive cases were considered.
By linkage studies in 3 extended Danish pedigrees using highly informative short tandem repeat polymorphisms, Eiberg et al. (1994) found linkage of the disease gene, which they symbolized OPA1, to a (CA)n dinucleotide repeat polymorphism at locus D3S1314; maximum lod = 10.34 at theta = 0.075. Using 2 additional chromosome 3 markers, they mapped the OPA1 gene in the region between D3S1314 and D3S1265: 3q28-qter. Lunkes et al. (1995) refined the localization of the OPA1 gene on 3q28-q29 to a region of 2-8 cM by studies in a Cuban pedigree with autosomal dominant optic atrophy of the KJER type.
Bonneau et al. (1995) confirmed the mapping of optic atrophy-1 to 3q28-qter, showing close linkage of the disease locus to 3 newly reported microsatellite DNA markers in 4 French families. There was no evidence of genetic heterogeneity.
In a study of 5 British pedigrees, Votruba et al. (1997) confirmed linkage to 3q28-q29 and narrowed the assignment to a 2-cM segment. In a large family in which Brown et al. (1997) found 34 affected members, linkage analysis revealed significant lod scores with 9 markers on 3q. The highest lod score, 10.1, was obtained with marker D3S2305. Analysis of recombinants narrowed the disease interval to approximately 3.8 cM, flanked by D3S3669 (centromeric) and D3S1305 (telomeric). Most affected members experienced loss of vision in the first decade of life and most progressed to 20/800 or poorer visual acuity by age 60, although 2 patients maintained visual acuities of 20/40 at that age. Similarly, by linkage analysis in a British family with 16 affected members, Johnston et al. (1997) mapped the OPA1 gene to the 3q27-q28 region. Votruba et al. (1998) further narrowed the optic atrophy-1 linkage interval on chromosome 3q28 to within 400 kb of the marker D3S1523, with a multipoint analysis maximum lod score of 8.01. They studied a total of 38 families with dominant optic atrophy, unrelated on the basis of genealogy, from a database of genetic eye disease families originating from the British isles. Allelic frequency analysis and haplotype parsimony analysis showed evidence of founder effect in 36 of the 38 pedigrees.
Heterogeneity
Heterogeneity within the group of autosomal dominant optic atrophy was suggested by linkage studies (Kivlin et al., 1983; Seller et al., 1997).
Alexander et al. (2000) and Delettre et al. (2000) independently identified a gene (OPA1; 605290) in the optic atrophy-1 candidate region that encodes a polypeptide with homology to dynamin-related GTPases. In patients with optic atrophy, both Alexander et al. (2000) and Delettre et al. (2000) identified mutations in the OPA1 gene (605290.0001-605290.0009).
Cohn et al. (2007) identified OPA1 mutations in 11 of 17 Australian pedigrees with autosomal dominant optic atrophy. The penetrance in the families with complete sib recruitment was 82.5%.
Using multiplex ligation probe amplification (MLPA), Fuhrmann et al. (2009) identified heterozygous deletions of 1 or more exons in the OPA1 gene in 5 of 42 OPA1 probands who did not have point mutations by previous screening techniques. Three additional probands had a heterozygous in-frame duplication of exons 7 to 9. Overall, the results were consistent with haploinsufficiency as the disease mechanism rather than gain of function. Fuhrmann et al. (2009) estimated that OPA1 genomic rearrangements have a prevalence of 12.9% in patients with autosomal dominant optic atrophy.
To define the prevalence and natural history of autosomal dominant optic atrophy, Yu-Wai-Man et al. (2010) performed a population-based epidemiologic and molecular study of 76 probands with a clinical diagnosis of autosomal dominant optic atrophy from the north of England. They detected OPA1 mutations in 57.6% of probands with a positive family history of optic atrophy (19/33) and in 14.0% of singleton cases (6/43). Approximately 2/3 of families with dominant optic atrophy harbored OPA1 mutations (14/22, 63%), and 5 novel OPA1 mutations were identified. Only 1 family carried a large-scale OPA1 rearrangement, and no OPA3 mutations were found in their optic atrophy cohort. OPA1 missense mutations were associated with a significantly worse visual outcome compared with other mutational subtypes (P = 0.0001).
Exclusion Studies
Votruba et al. (1998) excluded the candidate gene HRY (139605) as the causative gene for OPA on chromosome 3q.
'Belly spot and tail' (Bst) is a semidominant, homozygous lethal mutation in mouse that arose in the inbred strain C57BLKS (C57BL/Ks). Heterozygous mice have a kinky tail, white feet, and a white spot at the ventral midline. The phenotype arises from a deletion within the RPL24 (604180) riboprotein gene. In approximately 50% of the heterozygous mice, there is a reduction or a complete absence of the pupillary light reflex in one or both eyes (Rice et al., 1993). The basis of this phenotype is a unilateral or bilateral atrophy of the optic nerve. As in humans with optic atrophy-1, the severity of the atrophy of the optic nerves is highly variable, ranging from a slight reduction in the number of ganglion cell axons in 1 optic nerve to a complete elimination of both optic nerves. The surface area of the retina and the appearance of the inner and outer nuclear layers are qualitatively normal. Bst maps to chromosome 16 of the mouse (Epstein et al., 1986) in a region of homology to human chromosome 3 where the OPA1 gene is situated. Rice et al. (1995) did a refined mapping of this region by backcross analysis and found that the order of homologous loci in the mouse and human chromosomal maps suggested that OPA1 and Bst mapped to different regions of the conserved segment. However, they stated that the mutations may still be in the same gene and the gene order may have become altered within this segment.
Smith et al. (2000) reported an angiogenic phenotype in heterozygous Bst mice that was age-related, clinically evident, and resembled human subretinal neovascularization.
Davies et al. (2007) generated mutant mice carrying an ethylnitrosourea (ENU)-induced Q285X mutation in the Opa1 gene, resulting in a truncated protein. Western analysis showed that the mutation resulted in approximately 50% reduction in Opa1 protein in retina and all tissues. The homozygous mutation was embryonic lethal by 13.5 days postcoitum. Fibroblasts from adult heterozygotes showed an increase in mitochondrial fission and fragmentation. In addition, electron microscopy revealed the slow onset of optic nerve degeneration; reduced visual function in heterozygotes was demonstrated by optokinetic drum testing and the circadian running wheel. Davies et al. (2007) concluded that the OPA1 GTPase contains crucial information required for the survival of retinal ganglion cells and that OPA1 is essential for early embryonic survival.
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