Autosomal dominant optic atrophy

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Description from OMIM

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 Optic atrophy-2 (OPA2; 311050) maps to chromosome Xp11.4-p11.21. OPA3 (165300) is caused by mutation in the OPA3 gene (606580) on chromosome 19q13. OPA4 (605293) maps to chromosome 18q12.2-q12.3. OPA5 (610708) maps to chromosome 22q12.1-q13.1. OPA6 (258500) maps to chromosome 8q. OPA7 (612989) is caused by mutation in the TMEM126A gene (612988) on chromosome 11q14. OPA8 (616648) maps to chromosome 16q21-q22. OPA9 (616289) is caused by mutation in the ACO2 gene (100850) on chromosome 22q13; OPA10 (616732) is caused by mutation in the RTN4IP1 gene (610502) on chromosome 6q21; and OPA11 (617302) is caused by mutation in the YME1L1 gene (607472) on chromosome 10p12.

Prevalence of clinical parameters (%)

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Optic atrophy nervous 100 % 20837821 2011-10-18
Optic atrophy nervous 86 % 20157015 2011-10-12
Hearing loss nervous 63 % 20157015 2011-10-12
Ophthalmoplegia nervous 46 % 20157015 2011-10-12
Myopathy skeletal 36 % 20157015 2011-10-12
Ataxia nervous 30 % 20157015 2011-10-12
Neuropathy nervous 30 % 20157015 2011-10-12

List of references:

Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations.
Raffaele Lodi, Caterina Tonon, Maria Lucia Valentino, David Manners, Claudia Testa, Emil Malucelli, Chiara La Morgia, Piero Barboni, Michele Carbonelli, Simone Schimpf, Bernd Wissinger, Massimo Zeviani, Agostino Baruzzi, Rocco Liguori, Bruno Barbiroli, Valerio Carelli,

To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene.

Archives of neurology - Jan 2011

Multi-system neurological disease is common in patients with OPA1 mutations.
P Yu-Wai-Man, P G Griffiths, G S Gorman, C M Lourenco, A F Wright, M Auer-Grumbach, A Toscano, O Musumeci, M L Valentino, L Caporali, C Lamperti, C M Tallaksen, P Duffey, J Miller, R G Whittaker, M R Baker, M J Jackson, M P Clarke, B Dhillon, B Czermin, J D Stewart, G Hudson, P Reynier, D Bonneau, W Marques, G Lenaers, R McFarland, R W Taylor, D M Turnbull, M Votruba, M Zeviani, V Carelli, L A Bindoff, R Horvath, P Amati-Bonneau, P F Chinnery,

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Brain : a journal of neurology - Mar 2010