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 ... 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.
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 ... 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.
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 ... 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).
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 ... 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 100,00 when only OPA1-positive cases were considered.
Optic atrophy type 1 (OPA1 or Kjer type optic atrophy) is diagnosed in individuals with the following:...
DiagnosisClinical DiagnosisOptic atrophy type 1 (OPA1 or Kjer type optic atrophy) is diagnosed in individuals with the following:Bilateral vision loss that is usually symmetric Optic nerve pallor, the cardinal sign, usually bilateral and symmetric; temporal in about 50% of individuals and global in about 50% [Votruba et al 2003], particularly in older individuals and those with more severe involvement. In moderate cases, the optic atrophy may not be visible. Profound papillary excavation is reported in 21% of eyes with OPA1 [Alward 2003]. Visual field defect that is typically centrocecal, central, or paracentral; it is often large in individuals with severe disease. The peripheral field is usually normal, but inversion of red and blue isopters may occur. Note: The isopters are lines joining points of equal sensitivity on a visual field chart. The red isopter represents the largest/brightest stimulus; the blue isopter represents the smallest/dimmest stimulus. Persons with OPA1 have scotomas (areas of impaired visual acuity) in the central visual fields and sparing of the peripheral visual fields. Color vision defect, often described as acquired blue-yellow loss (tritanopia) Childhood onset Family history consistent with autosomal dominant inheritance The systematic molecular genetic testing of OPA1 in persons with autosomal dominant optic atrophy (ADOA) has revealed a wide range of clinical manifestations. Up to 10% of persons with an OPA1 mutation have additional extra-ophthalmologic abnormalities, most commonly sensorineural hearing loss, ataxia, and myopathy (see Clinical Description). Electrophysiology Visual evoked potentials (VEPs) are typically absent or delayed, indicating a conduction defect in the optic nerve. Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform [Holder et al 1998]. Since the N95 component of the PERG is thought to be specific for the retinal ganglion cell, this finding supports a ganglion cell origin for the optic atrophy. Note: The PERG originates from the inner retinal layers, enabling an assessment of ganglion cell function, and is increasingly used in the assessment of anterior visual pathway dysfunction. The normal PERG consists of a prominent positive peak at 50 ms (P50), and a slow, broad trough with a minimum at 95 ms (N95). The positive P50 component is invariably affected in retinal and macular dysfunction, whereas the negative N95 component is principally affected in optic nerve disease. Furthermore, the ratio between N95 and P50 has been shown to be an effective measure of retinal ganglion cell function.Molecular Genetic TestingGene. OPA1 is the only gene known to be associated with optic atrophy type 1 [Alexander et al 2000, Delettre et al 2000]. Other loci. Because the detection rate for mutations in OPA1 is less than 100%, it is possible that families in which a mutation is not detected are not linked to the OPA1 locus; however, no evidence supports this possibility.Clinical testing Sequence analysis/mutation scanning of all exons and flanking intron junctions from genomic DNA of OPA1 Sequence analysis of cDNA. RT-PCR amplification performed on OPA1 mRNA extracted from blood creates cDNA that can be sequenced to characterize splice-site mutations and abnormally spliced forms. Deletion/duplication analysis. OPA1 deletions involving multiple and single exons, and even the entire gene, have been reported. See Table A. Genes and Databases.Targeted mutation analysis for the Danish founder mutationTable 1. Summary of Molecular Genetic Testing Used in Optic Atrophy Type 1View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2Test AvailabilityFamilialSimplex 3 OPA1Sequence analysis / mutation scanning 4Sequence variants 58/9 610/14 717/19 84/8 6ClinicalTargeted mutation analysisDanish founder mutation c.2826delT UnknownUnknownDeletion/duplication analysis 9Exonic or whole-gene deletionsUnknown Unknown 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. The theoretic possibilities of locus heterogeneity or presence of a large gene deletion not detected by sequence analysis may account for a detection rate less than 100% (see Interpretation of test results).3. Simplex = a single occurrence in a family4. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.6. Nakamura et al [2006] found OPA1 mutations in 8/9 familial cases and 4/8 simplex cases. Of note, on examination of family members of two apparently simplex cases, Nakamura et al [2006] found OPA1 mutations in relatives with a normal or only mildly abnormal phenotype, supporting the notions of variable expressivity and reduced penetrance.7. Puomila et al [2005]8. Delettre et al [2001]9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a probandAn individual suspected of having optic atrophy type 1 should have molecular genetic testing of OPA1. If no mutation is identified, molecular genetic testing of OPA3 for autosomal dominant optic atrophy type 3 (OPA3) and for the common mitochondrial DNA (mtDNA) point mutations responsible for Leber hereditary optic neuropathy (LHON) should be performed. See Differential Diagnosis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNormal allelic sequence variants in OPA1 may be associated with normal tension glaucoma (NTG), which could be considered a genetically determined optic neuropathy with similarities to both Leber hereditary optic neuropathy (LHON) and OPA1 [Yu-Wai-Man et al 2010].
Variable expressivity of optic atrophy type 1 (OPA1) is observed both between and within families. ...
Natural HistoryVariable expressivity of optic atrophy type 1 (OPA1) is observed both between and within families. Vision loss. OPA1 usually presents as insidious decrease in visual acuity between ages four and six years; in mild cases visual acuity may remain normal until early adult life. Visual acuity usually declines slowly with age. Although rare, rapid decline in visual acuity has been reported in adults [Kjer et al 1996]. The visual impairment is usually moderate (6/10 to 2/10), but ranges from severe (legal blindness with acuity <1/20) to mild or even insignificant, and consequently can be underestimated. The vision loss is occasionally asymmetric. Typical ADOA is associated with a progressive and irreversible loss of vision. However, Cornille et al [2008] reported a 23-year-old man who developed unexplained isolated, progressive, painless bilateral optic neuropathy as a result of central scotomas (visual acuity 20/200 in the right eye and 20/100 in the left eye) three months after the first signs of visual loss. Six months later he had spontaneous and durable partial recovery of visual acuity (20/30 in the right eye and 20/25 in the left eye). The patient harbored a heterozygous mutation in exon 5b (c.740G>A), which was the first mutation to be described in one of the three alternative OPA1 exons, leading to an amino acid change in the N-terminal coiled coil domain (p.Arg247His) from isoform 8. Extra-ophthalmogic findings. Up to 10% of persons with an OPA1 mutation have additional extra-ophthalmologic abnormalities, most commonly sensorineural hearing loss, ataxia, and myopathy, suggesting that mutation of OPA1 may be responsible for a continuum of phenotypes ranging from mild disorders affecting only the retinal ganglion cells to a severe and multisystemic disease.Sensorineural hearing loss that ranges from severe and congenital to subclinical (requiring specific testing for detection) has been reported along with optic atrophy in a few families or individuals with the p.Arg445His mutation in OPA1 [Amati-Bonneau et al 2003, Amati-Bonneau et al 2005]. Amati-Bonneau et al [2005] concluded that the hearing loss resulted from auditory neuropathy. In an individual with the p.Arg445His mutation, auditory brain stem responses (ABRs) were absent and both ears had normal evoked otoacoustic emissions. Because evoked otoacoustic emissions reflect the functional state of presynaptic elements (the outer hair cells), and the ABRs reflect the integrity of the auditory pathway from the auditory nerve to the inferior colliculus, the presence of evoked otoacoustic emissions and the lack of ABRs support the diagnosis of auditory neuropathy. Both intra- and interfamilial variation in the presence of hearing loss with optic atrophy have been observed. Furthermore, the p.Arg445His mutation was associated with optic atrophy without hearing loss in a 21-year-old Japanese individual; no other family member was clinically affected or had the OPA1 mutation [Shimizu et al 2003]. Treft et al [1984] and Meire et al [1985] reported two unrelated families with autosomal dominant optic atrophy, hearing loss, ptosis, and ophthalmoplegia. Subsequent studies revealed the p.Arg445His mutation in OPA1 in both families [Payne et al 2004]. Li et al [2005] identified the p.Arg445His mutation in a family with optic atrophy and hearing loss, without ptosis or ocular motility abnormalities. These family members are also myopic, but it is not clear if myopia is part of the phenotype. Ataxia and myopathy. Some individuals developed proximal myopathy (35%), a combination of cerebellar and sensory ataxia in adulthood (29%), and axonal sensory and/or motor neuropathy (29%). These features became manifest from the third decade of life onwards.Muscle biopsy revealed features diagnostic of mitochondrial myopathy. In these individuals approximately 10% of all fibers were deficient in histochemical COX activity and several fibers showing evidence of subsarcolemmal accumulation of abnormal mitochondria. Pathology. The cardinal sign of OPA1 is optic atrophy that appears as bilateral and generally symmetric temporal pallor of the optic disc, implying the loss of central retinal ganglion cells. Histopathology. Histopathology shows a normal outer retina and loss of retinal ganglion cells, primarily in the macula and in the papillo-macular bundle of the optic nerve.
No correlation has been observed between the degree of visual impairment and the location or type of mutation [Puomila et al 2005]. ...
Genotype-Phenotype CorrelationsNo correlation has been observed between the degree of visual impairment and the location or type of mutation [Puomila et al 2005]. Complete deletion of OPA1 results in typical dominant optic atrophy without predictable severity or other deficits [Marchbank et al 2002]. However, it seems that in-frame deletions involve loss of visual acuity (1/10 on average) that is statistically slightly more severe than that resulting from truncating mutations or missense substitutions (2/10 on average) [Ait Ali et al, unpublished].
OPA3.OPA3 consists of three exons and encodes for an inner mitochondrial membrane protein. The function of this protein is not well known. Two disorders are associated with OPA3 mutations: ...
Differential DiagnosisOPA3. OPA3 consists of three exons and encodes for an inner mitochondrial membrane protein. The function of this protein is not well known. Two disorders are associated with OPA3 mutations: Costeff optic atrophy syndrome. Truncating mutations are responsible for 3-methylglutaconic aciduria type 3, also called Costeff optic atrophy syndrome, a neuroophthalmologic syndrome consisting of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methglutaric acid is increased. Inheritance is autosomal recessive. Autosomal optic atrophy and cataract (ADOAC, OPA3). Reynier et al [2004] have identified two causative mutations in OPA3 (p.Gly93Ser and p.Gln105Glu) that change one of the amino acids. Inheritance is autosomal dominant. Leber hereditary optic neuropathy (LHON) is the major differential diagnosis for optic atrophy type 1 (OPA1). LHON typically presents in young adults as painless subacute bilateral visual failure. Males are more commonly affected than females. Women tend to develop the disorder slightly later in life and may be more severely affected. The acute phase begins with blurring of central vision and color desaturation that affect both eyes simultaneously in up to 50% of cases. After the initial symptoms, both eyes are usually affected within six months. The central visual acuity deteriorates to the level of counting fingers in up to 80% of cases. Following the nadir, acuity may improve. Individuals then proceed into the atrophic phase and are usually legally blind for the rest of their lives with a permanent large centrocecal scotoma. Minor neurologic abnormalities (such as a postural tremor or the loss of ankle reflexes) are said to be common in individuals with LHON. Some individuals with LHON, usually women, also have a multiple sclerosis (MS)-like illness. LHON is inherited by mitochondrial inheritance. In one large study, 95% of individuals with LHON were found to have one of three point mutations of mtDNA: m.11778G>A, m.14484T>C, m.3460G>A. Autosomal dominant optic atrophy (ADOA). Two other loci associated with autosomal dominant optic atrophy have been identified: OPA4 (OMIM 605293) was mapped to 8q12.2-q12.3 in a single large family by Kerrison et al [1999]; however, the locus has not been confirmed and the disease gene is still unknown. OPA5 was mapped to 22q12.1-q13.1 by Barbet et al [2005] in two unrelated families. The phenotype of the three families with OPA4 or OPA5 is comparable to the phenotype seen in OPA1: optic nerve pallor, decreased visual acuity, color vision defects, impaired VEP, and normal ERG. No extraocular findings were described in these families. Another OPA locus for ADOA was mapped to 16q21-q22 in one Italian family with extraophthalmologic features extending to the auditory system [Carelli et al 2007].The gene in which mutation is causative is unknown. Deafness-dystonia-optic neuronopathy syndrome (DDON). Males with DDON have prelingual or postlingual sensorineural hearing impairment, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning about age 20 years, and dementia beginning at about age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment phenotype is a progressive auditory neuropathy, while the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia. Inheritance is X-linked. The DDON syndrome occurs as either a single-gene disorder resulting from mutation in TIMM8A or a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia caused by disruption of BTK, located telomeric to TIMM8A. WFS1. Mutations in WFS1 are generally associated with optic atrophy (OPA) as part of the autosomal recessive Wolfram syndrome phenotype (DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, deafness]) or with autosomal dominant progressive low-frequency sensorineural hearing loss (LFSNHL) without ophthalmologic abnormalities [Cryns et al 2003]. However, Eiberg et al [2006] identified a WFS1 mutation associated with autosomal dominant optic atrophy, hearing loss, and impaired glucose regulation in one family, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to optic atrophy combined with hearing impairment. (See WFS1-Related Disorders).MFN2. Charcot-Marie-Tooth (CMT) neuropathy type 2A2 (see CMT2A) with visual impairment resulting from optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI) [Voo et al 2003]. Zuchner et al [2006] described six families with HMSN VI with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of affected individuals. In each pedigree a unique mutation in MFN2, encoding mitofusin 2, was identified. Inheritance is autosomal dominant. Other optic neuropathies. The acquired blue-yellow loss (tritanopia) helps differentiate OPA1 from other optic neuropathies in which the axis of confusion is red-green: OPA2. A gene for X-linked optic atrophy (OPA2) has been mapped to chromosome Xp11.4-p11.21; to date no gene has been identified. OPA6. The first locus for isolated autosomal recessive optic atrophy (ROA1) has been mapped to chromosome 8q. Dyschromatopsia for red-green confusion occurs in OPA6. OPA7. Hanein et al [2009] identified an autosomal recessive juvenile-onset optic atrophy in a large multiplex inbred Algerian family and subsequently in three other Maghreb families. This form of optic atrophy is caused by mutation in TMEM126A (chromosome 11q14.1-q21) that encodes a mitochondrial protein found in higher eukaryotes that has four transmembrane domains and a central domain conserved with the related protein encoded by TMEM126B.Acquired optic neuropathy can be caused by the following: Nutritional deficiencies of protein, or of the B vitamins and folate, associated with starvation, malabsorption, or alcoholism Toxic exposures. The most common is "tobacco-alcohol amblyopia," thought to be caused by exposure to cyanide from tobacco smoking, and by low levels of vitamin B12 caused by poor nutrition and poor absorption associated with drinking alcohol. Other possible toxins include ethambutol, methyl alcohol, ethylene glycol, cyanide, lead, and carbon monoxide. Certain medications
In order to establish the extent of disease in an individual with optic atrophy type 1 (OPA1), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisIn order to establish the extent of disease in an individual with optic atrophy type 1 (OPA1), the following evaluations are recommended:Assessment of visual acuity, color vision, and visual fields Assessment of extraocular muscles (the patient is asked to follow the ophthalmoscope with his/her eyes without moving the head) Hearing evaluation: auditory brain stem responses (ABRs), auditory evoked potentials (AEPs), and evoked otoacoustic emissions Oral glucose tolerance test Treatment of ManifestationsNo treatment is of proven efficacy for OPA1.Treatment of decreased visual acuity is symptomatic (e.g., low-vision aids).For treatment of sensorineural hearing loss, see Deafness and Hereditary Hearing Loss Overview.For treatment of ataxia, see Ataxia Overview.SurveillanceAppropriate surveillance includes:Annual ophthalmologic examination Annual hearing evaluation Agents/Circumstances to AvoidIndividuals with an OPA1 mutation are advised:Not to smoke To moderate their alcohol intake To use sunglasses to limit UV exposure (Note: While limiting UV exposure is a good practice, no evidence for its effectiveness exists.) Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Optic Atrophy Type 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDOPA13q29Dynamin-like 120 kDa protein, mitochondrialAutosomal Dominant Optic Atrophy (eOPA1) at LBBMA Retina International Mutations of the Optic Atrophy 1 Gene (OPA1)OPA1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Optic Atrophy Type 1 (View All in OMIM) View in own window 165500OPTIC ATROPHY 1; OPA1 605290OPA1 GENE; OPA1Molecular Genetic PathogenesisBecause OPA1 expression is ubiquitous, and it was recently proposed that neither the pattern nor the abundance of OPA1 mRNA and dynamin-like 120-kd protein variants are specific to retinal ganglion cell (RGC) [Kamei et al 2005], a plausible hypothesis as to why these neurons may be more vulnerable to OPA1 inactivation could be a particular susceptibility to mitochondrial membrane disorders inducing mitochondrial dysfunction or mislocalization. While the former point is in agreement with reports that describe altered mitochondrial ATP synthesis and respiration in OPA1-inactivated cells [Lodi et al 2004, Amati-Bonneau et al 2005, Chen et al 2005], the latter may relate to the particular distribution of the mitochondria in retinal ganglion cells. These show an accumulation of mitochondria in the cell bodies and in the intraretinal unmyelinated axons, where they accumulate in the varicosities, and a relative paucity of mitochondria in the myelinated parts of axons [Andrews et al 1999, Bristow et al 2002, Wang et al 2003]. Furthermore, the effect of mitochondrial dynamics on the correct intracellular distribution of the mitochondria and its influence on neuronal plasticity and function was recently highlighted by inactivation of DRP1 in live hippocampal neurons [Li et al 2004]. A link between axonal transport of mitochondria [Hollenbeck & Saxton 2005] and mitochondrial dynamics was also enlightened by a recent study showing that Drosophila mutants lacking the ortholog of human DRP1 protein failed to populate the distal axon with mitochondria, affecting the mobilization of the synaptic vesicle reserve pool [Hollenbeck 2005]. Moreover, mutations in the pro-fusion protein encoded by MFN2, which cause a peripheral neuropathy (see CMT2A) [Zuchner et al 2006], significantly impaired the transport of mitochondria in axons in neurons expressing disease-mutated forms of MFN2 [Baloh et al 2007]. These data suggest that proper localization of mitochondria is critical for axonal and synaptic function. Normal allelic variants. OPA1 consists of 31 exons spanning more than 114 kb of genomic DNA. Eight isoforms have been described as a result of alternative splicing of exons 4, 4b, and 5b [Delettre et al 2001]. Pathologic allelic variants. There is a wide spectrum of mutations, with over 213 reported to date (see eOPA1, an online database for OPA1 mutations). The OPA1 mutations are spread throughout the gene coding sequence, but most are localized in GTPase domain (exons 8-16) and in the 3' end of the coding region (exons 27-28), whereas few mutations are found in exons 1 to 7. To date no mutations have been found in exons 4 and 4b, which are alternatively spliced. See Table A. However, a heterozygous mutation in exon 5b (c.740G>A) has been described in one affected individual [Cornille et al 2008]. An Alu-element insertion located in intron 7 of OPA1 has been described to cause an in-frame deletion of exon 8 in a family with ADOA [Gallus et al 2010]. Table 2. Selected OPA1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference Sequences c.740G>Ap.Arg247HisNM_130837.2 NP_570850.2 isoform 8c.1065+1G>T (IVS12+1G>T)--NM_015560.2 NP_056375.2 isoform 1c.1334G>A p.Arg445Hisc.2708_2711delTTAGp.Val903Glyfs*3c.2826delTp.Arg943Glufs*25See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. Dynamin-like 120-kd protein (OPA1), encoded by OPA1, is a mitochondrial dynamin-related GTP protein of 960 amino acids. This is the first dynamin-related protein found to be involved in human disease. The dynamin-like 120-kd protein comprises a highly basic amino-terminal that provides mitochondrial targeting sequence (MTS), a dynamin-GTPase domain, and a C-terminus of unknown function; the C-terminus differs from that of other dynamin family members in lacking a proline-rich region, a dynamin GTPase effector domain, and a pleckstrin homology domain; the C-terminus may therefore determine the specific functions of the dynamin-like 120-kd protein. OPA1 appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. Downregulation of OPA1 leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential with cytochrome c release and caspase-dependent apoptosis [Olichon et al 2003]. Mitochondrial DNA (mtDNA) deletions have recently been identified in families with autosomal dominant optic atrophy who have complex multisystem involvement in addition to the optic neuropathy [Amati-Bonneau et al 2008; Ferraris et al 2008; Hudson et al 2008] suggesting a role of OPA1 in mtDNA maintenance.Abnormal gene product. The functional consequences of mutations in OPA1 are unknown. Since almost 50% of mutations predict protein truncation, dominant inheritance of the disease may result from haploinsufficiency of dynamin-like 120-kd protein. However, missense mutations can also cause disease by a dominant-negative mechanism.Interestingly, evidence for a dominant-negative mechanism has been reported in all the multi-systemic forms of the disease (ADOAD and “ADOA plus”). These disease forms have missense mutations affecting the GTPase domain [Amati-Bonneau et al 2008]. In addition, one person with ADOA, who was a compound heterozygote for two OPA1 missense mutations located in exon 8, was found to be severely affected by the disease [Pesch et al 2001], whereas her heterozygous parents and siblings were less severely affected, suggesting a semi-dominant mode of inheritance in this family.