Alternative titles; symbols
SNOMEDCT: 715374003; ORPHA: 1215, 3212; DO: 0111340;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q29 | Optic atrophy plus syndrome | 125250 | Autosomal dominant | 3 | OPA1 | 605290 |
A number sign (#) is used with this entry because of evidence that this syndromic form of optic atrophy is caused by heterozygous mutation in the OPA1 gene (605290) on chromosome 3q29. Some patients with biallelic OPA1 mutations have a more severe phenotype with earlier onset.
See also optic atrophy-1 (OPA1; 165500), which is an allelic disorder without extraocular neurologic complications.
Syndromic optic atrophy, also known as DOA+ syndrome, is a neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia (PEO), muscle cramps, hyperreflexia, and ataxia. There appears to be a wide range of intermediate phenotypes (Yu-Wai-Man et al., 2010).
Konigsmark et al. (1974, 1974) described an association of congenital deafness with late-onset, progressive optic atrophy which resulted in only mildly reduced visual acuity. Six persons in 4 generations were affected. No male-to-male transmission was noted. However, males and females were equally severely affected and a daughter of an affected male was not affected. Gernet (1964) reported the same disorder in mother and daughter.
In 23 members of 5 generations of a family, Treft et al. (1984) described a syndrome of early-onset optic atrophy and deafness. Some patients developed ophthalmoplegia, ptosis, ataxia, and nonspecific myopathy in middle age. The optic atrophy was progressive and associated with an abnormal electroretinogram without retinal pigment changes. The hearing loss was also progressive and sensorineural in type, usually becoming evident in the first or second decade of life. Many of the features suggested the Kearns-Sayre syndrome (530000), but the involvement of the son of the propositus, the only instance of male-to-male transmission, appeared to rule out a mitochondrial causation.
Shimizu et al. (2003) reported a Japanese patient with optic atrophy and moderate hearing loss in both ears.
Amati-Bonneau et al. (2005) found fragmentation of the mitochondrial network and defects in oxidative phosphorylation in skin fibroblasts from 5 patients with optic atrophy and deafness.
Hudson et al. (2008) reported 7 affected members from a family with optic atrophy, ataxia, and external ophthalmoplegia and variable presentation of hearing loss, myopathy, and neuropathy.
Ferraris et al. (2008) reported a 42-year-old man with PEO, loss of central vision, sensorineural deafness, and mild ataxia. Other features included macrocytic anemia and hypogonadism. Muscle biopsy showed mild variation in fiber size, atrophic fibers, and multiple mitochondrial DNA deletions. Although no ragged-red fibers were identified, several fibers were devoid of cytochrome-c oxidase activity.
Marelli et al. (2011) reported 2 adult brothers who presented with optic atrophy resulting in progressive visual loss in the first decade, followed by progressive spastic pyramidal syndrome and mild cerebellar ataxia resulting in gait difficulties in the second decade. Both had distal vibratory impairment, and 1 had urinary problems. Disease progression was very slow and they were still ambulatory in the mid-forties. There was no cognitive impairment; brain imaging showed mild cerebellar atrophy. Muscle biopsy showed only a few COX-negative fibers and no mitochondrial DNA deletions. Molecular studies identified a heterozygous missense mutation in the OPA1 gene (C551Y; 605290.0019). Both parents were unaffected, suggesting autosomal dominant inheritance with incomplete penetrance or a de novo mutation with gonadal mosaicism. Marelli et al. (2011) noted that spastic paraplegia had been reported in this disorder by Yu-Wai-Man et al. (2010), and also noted that the phenotype was consistent with a clinical diagnosis of Behr syndrome (BEHRS; 210000), although that disorder usually shows an autosomal recessive pattern of transmission.
Napolitano et al. (2020) reported affected mother and daughter. The 27-year-old daughter had reduced visual acuity, deafness, and myopathy, and the 57-year-old mother had amaurosis, deafness, extraocular muscle palsy, and ataxia. Respiratory chain activity of complexes I, I+III, II+III, and IV were decreased in muscle tissue from the daughter, and activity of complexes I+III, II+III, and IV were decreased in muscle tissue from the mother. Muscle tissue from both patients demonstrated the presence of COX-negative fibers and abnormal-appearing mitochondria.
Verny et al. (2008) reported a patient with genetically-confirmed OPA1 who presented with a phenotype suggestive of multiple sclerosis (MS; 126200). He developed bilateral loss of visual acuity at age 43, followed by pain in the lower left limb and trigeminal neuralgia. Neurologic examination showed brisk tendon reflexes, spastic gait, and clonus in the left lower limb. MRI scan showed high intensity lesions in the cerebrum and spinal cord. Mitochondrial studies demonstrated severely impaired respiration and decreased ATP synthesis, which the authors postulated may have led to central demyelination in this patient.
Yu-Wai-Man et al. (2010) reported the results of a large multicenter study of 104 patients from 45 families with OPA1 mutations, including 60 new cases. Extraocular neurologic complications were common, and affected up to 20% of all mutation carriers. The most prominent manifestation after optic neuropathy (85.6%) was bilateral sensorineural deafness (62.5%) beginning in late childhood and early adulthood, followed by a combination of ataxia (29.8%), myopathy (35.6%), peripheral neuropathy (29.8%), and progressive external ophthalmoplegia (46.2%). These additional features became manifest from the third decade of life onwards. Spastic paraparesis was reported in 2 families, and a multiple sclerosis-like disorder was reported in 2 families, including the previously reported patient of Verny et al. (2008).
The transmission pattern of DOA+ in the family reported by Marelli et al. (2011) was consistent with autosomal dominant inheritance.
In a Japanese patient with optic atrophy and moderate hearing loss, Shimizu et al. (2003) identified a heterozygous mutation in the OPA1 gene (R445H; 605290.0011).
Payne et al. (2004) identified the R445H mutation in the large Utah family with dominantly inherited optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia, originally described by Treft et al. (1984), and in an unrelated Belgian family with a similar phenotype, originally reported by Meire et al. (1985).
Li et al. (2005) identified the R445H mutation in another family with optic atrophy and hearing loss and noted that affected members of this family did not have extraocular motility abnormalities or ptosis, thus illustrating the intra- and interfamilial phenotype variability associated with this mutation.
Amati-Bonneau et al. (2005) identified the R445H mutation in 5 patients from 4 unrelated families with optic atrophy and deafness, thus confirming that this mutation is specifically associated with hearing loss. One of the patients had previously been reported by Amati-Bonneau et al. (2003). In the Spanish mother and daughter previously reported by Amati-Bonneau et al. (2005), Amati-Bonneau et al. (2008) noted that the mother also had myopathy, neuropathy, and progressive external ophthalmoplegia.
In a patient with sporadic occurrence of progressive external ophthalmoplegia (PEO), hearing loss, mild myopathy, and ataxia, Ferraris et al. (2008) identified a heterozygous mutation in the OPA1 gene (605290.0013).
Stewart et al. (2008) identified mutations in the OPA1 gene (605290.0011 and 605290.0014) in 3 (14.2%) of 21 probands with mitochondrial DNA deletions. The probands had optic atrophy, variable deafness, and myopathy. The findings confirmed the report by Ferraris et al. (2008) that OPA1 mutation may cause multiple mtDNA deletions and myopathy.
Hudson et al. (2008) identified a heterozygous mutation (605290.0015) in 7 affected members of a family with optic atrophy, ataxia, and external ophthalmoplegia and variable presentation of hearing loss, myopathy, and neuropathy. Yu-Wai-Man et al. (2010) identified the same heterozygous mutation in 3 affected members of an Austrian family with optic atrophy, ataxia, and external ophthalmoplegia with variable presentation of deafness and neuropathy and in French proband with optic atrophy, deafness, ataxia, myopathy, and neuropathy.
Amati-Bonneau et al. (2008) identified a heterozygous mutation (605290.0016) in an Italian father and daughter with optic atrophy and deafness. The father also had ataxia, myopathy, neuropathy, and PEO.
In 2 adult brothers with optic atrophy, cerebellar ataxia, spasticity, and neuropathy, Marelli et al. (2011) identified a heterozygous missense mutation in the OPA1 gene (C551Y; 605290.0019). Functional studies of the variant were not performed.
In a 27-year-old Italian woman and her 57-year-old mother with DOA+, Napolitano et al. (2020) identified heterozygosity for a missense mutation in the OPA1 gene (R445H; 605290.0011). The daughter had reduced visual acuity, deafness, and myopathy, and her mother had amaurosis, deafness, extraocular muscle palsy, and severe ataxia. Expression of HTRA2 (606441) was increased in the muscle tissue of both patients, although more so in the daughter. Napolitano et al. (2020) hypothesized that OPA1 mutations may induce HTRA2 overexpression, and variable expression of HTRA2 may contribute to disease variability in optic atrophy and deafness in patients with the same OPA1 mutation.
Among 104 patients from 45 families with 33 different OPA1 mutations, Yu-Wai-Man et al. (2010) found that multisystem neurologic disease was associated with all types of mutations; however, there was an increased risk with missense mutations (odds ratio (OR) of 3.06; p = 0.0027) and with mutations located within the GTPase region (OR of 2.29; p = 0.0271). Skeletal muscle biopsies from those with extraocular neurologic features showed higher levels of cytochrome c oxidase-deficient fibers and mitochondrial DNA deletions compared to those with pure optic neuropathy, suggesting a causal role for these secondary mitochondrial DNA defects in disease pathophysiology.
Amati-Bonneau, P., Guichet, A., Olichon, A., Chevrollier, A., Viala, F., Miot, S., Ayuso, C., Odent, S., Arrouet, C., Verny, C., Calmels, M.-N., Simard, G., Belenguer, P., Wang, J., Puel, J.-L., Hamel, C., Malthiery, Y., Bonneau, D., Lenaers, G., Reynier, P. OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann. Neurol. 58: 958-963, 2005. [PubMed: 16240368] [Full Text: https://doi.org/10.1002/ana.20681]
Amati-Bonneau, P., Odent, S., Derrien, C., Pasquier, L., Malthiery, Y., Reynier, P., Bonneau, D. The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene. Am. J. Ophthal. 136: 1170-1171, 2003. [PubMed: 14644237] [Full Text: https://doi.org/10.1016/s0002-9394(03)00665-2]
Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissiere, A., Campos, Y., Rivera, H., de la Aleja, J. G., Carroccia, R., Iommarini, L., Labauge, P., and 22 others. OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes. Brain 131: 338-351, 2008. [PubMed: 18158317] [Full Text: https://doi.org/10.1093/brain/awm298]
Ferraris, S., Clark, S., Garelli, E., Davidzon, G., Moore, S. A., Kardon, R. H., Bienstock, R. J., Longley, M. J., Mancuso, M., Rios, P. G., Hirano, M., Copeland, W. C., DiMauro, S. Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1. Arch. Neurol. 65: 125-131, 2008. [PubMed: 18195150] [Full Text: https://doi.org/10.1001/archneurol.2007.9]
Gernet, H. Hereditaere Opticusatrophie in Kombination mit Taubheit. Dtsch. Ophthal. Ges. 65: 545-547, 1964.
Hudson, G., Amati-Bonneau, P., Blakely, E. L., Stewart, J. D., He, L., Schaefer, A. M., Griffiths, P. G., Ahlqvist, K., Suomalainen, A., Reynier, P., McFarland, R., Turnbull, D. M., Chinnery, P. F., Taylor, R. W. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness, and multiple mitochondrial deletions: a novel disorder of mtDNA maintenance. Brain 131: 329-337, 2008. [PubMed: 18065439] [Full Text: https://doi.org/10.1093/brain/awm272]
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Konigsmark, B. W., Knox, D. L., Hussels, I. E., Moses, H. Dominant congenital deafness and progressive optic nerve atrophy. Arch. Ophthal. 91: 99-103, 1974. [PubMed: 4544000] [Full Text: https://doi.org/10.1001/archopht.1974.03900060105003]
Li, C., Kosmorsky, G., Zhang, K., Katz, B. J., Ge, J., Traboulsi, E. I. Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation. Am. J. Med. Genet. 138A: 208-211, 2005. [PubMed: 16158427] [Full Text: https://doi.org/10.1002/ajmg.a.30794]
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Meire, F., De Laey, J. J., de Bie, S., van Staey, M., Matton, M. T. Dominant optic nerve atrophy with progressive hearing loss and chronic progressive external ophthalmoplegia (CPEO). Ophthalmic Paediat. Genet. 5: 91-97, 1985. [PubMed: 4058877] [Full Text: https://doi.org/10.3109/13816818509007861]
Napolitano, F., Terracciano, C., Bruno, G., Nesti, C., Barillari, M. R., Barillari, U., Santorelli, F. M., Melone, M. A. B., Esposito, T., Sampaolo, S. Intrafamilial 'DOA-plus' phenotype variability related to different OMI/HTRA2 expression. Am. J. Med. Genet. 182A: 176-182, 2020. [PubMed: 31609081] [Full Text: https://doi.org/10.1002/ajmg.a.61381]
Payne, M., Yang, Z., Katz, B. J., Warner, J. E. A., Weight, C. J., Zhao, Y., Pearson, E. D., Treft, R. L., Hillman, T., Kennedy, R. J., Meire, F. M., Zhang, K. Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1. Am. J. Ophthal. 138: 749-755, 2004. [PubMed: 15531309] [Full Text: https://doi.org/10.1016/j.ajo.2004.06.011]
Shimizu, S., Mori, N., Kishi, M., Sugata, H., Tsuda, A., Kubota, N. A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy. Am. J. Ophthal. 135: 256-257, 2003. [PubMed: 12566046] [Full Text: https://doi.org/10.1016/s0002-9394(02)01929-3]
Stewart, J. D., Hudson, G., Yu-Wai-Man, P., Blakeley, E. L., He, L., Horvath, R., Maddison, P., Wright, A., Griffiths, P. G., Turnbull, D. M., Taylor, R. W., Chinnery, P. F. OPA1 in multiple mitochondrial DNA deletion disorders. Neurology 71: 1829-1831, 2008. [PubMed: 19029523] [Full Text: https://doi.org/10.1212/01.wnl.0000335931.54095.0a]
Treft, R. L., Sanborn, G. E., Carey, J., Swartz, M., Crisp, D., Wester, D. C., Creel, D. Dominant optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy: a new syndrome. Ophthalmology 91: 908-915, 1984. [PubMed: 6493699] [Full Text: https://doi.org/10.1016/s0161-6420(84)34214-2]
Verny, C., Loiseau, D., Scherer, C., Lejeune, P., Chevrollier, A., Gueguen, N., Guillet, V., Dubas, F., Reynier, P., Amati-Bonneau, P., Bonneau, D. Multiple sclerosis-like disorder in OPA1-related autosomal dominant optic atrophy. Neurology 70: 1152-1153, 2008. [PubMed: 18287570] [Full Text: https://doi.org/10.1212/01.wnl.0000289194.89359.a1]
Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., Toscano, A., Musumeci, O., Valentino, M. L., Caporali, L., Lamperti, C., Tallaksen, C. M., and 24 others. Multi-system neurological disease is common in patients with OPA1 mutations. Brain 133: 771-786, 2010. [PubMed: 20157015] [Full Text: https://doi.org/10.1093/brain/awq007]