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Lookup NU author(s): Dr Patrick Yu Wai Man, Philip Griffiths, Professor Grainne Gorman, Professor Roger Whittaker, Professor Mark BakerORCiD, Dr Margaret Jackson, Michael Clarke, Professor Gavin Hudson, Professor Bobby McFarlandORCiD, Professor Robert Taylor, Emeritus Professor Doug Turnbull, Professor Rita HorvathORCiD, Professor Patrick 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.
Author(s): Yu Wai Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2010
Volume: 133
Issue: 3
Pages: 771-786
Print publication date: 01/03/2010
Date deposited: 19/07/2010
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/brain/awq007
DOI: 10.1093/brain/awq007
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