#165500
ICD+
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| OPTIC ATROPHY 1; OPA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPTIC ATROPHY, JUVENILE KJER-TYPE OPTIC ATROPHY OPTIC ATROPHY, KJER TYPE; OAK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Phenotypic Series | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because optic atrophy-1 is caused by heterozygous mutation in the gene encoding the human homolog of the S. pombe dynamin-related protein Msp1 (OPA1; 605290) on chromosome 3q28-q29. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 Another locus for optic atrophy, OPA2 (311050), has been mapped to chromosome Xp11.4-p11.21. Optic atrophy-3 (OPA3; 165300) is caused by mutation in the OPA3 gene (606580) on chromosome 19q13.2-q13.3. Optic atrophy-4 (OPA4; 605293) has been mapped to chromosome 18q12.2-q12.3, Optic atrophy-5 (OPA5; 610708) to chromosome 22q12.1-q13.1, and optic atrophy-6 (OPA6; 258500) to chromosome 8q. Optic atrophy-7 (OPA7; 612989) is caused by mutation in the TMEM126A gene (612988) on chromosome 11q14.1-q21. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathogenesis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. Votruba et al. (1998) excluded the candidate gene HRY (139605), which maps to the same region of 3q. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| '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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Brodrick (1974); Kjer (1959); Smith (1972); Verny et al. (2008) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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