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. CzerminJ. 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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)771-786
Number of pages16
JournalBrain
Volume133
DOIs
Publication statusPublished - Mar 2010

Cite this

Yu-Wai-Man, P., Griffiths, P. G., Gorman, G. S., Lourenco, C. M., Wright, A. F., Auer-Grumbach, M., ... Chinnery, P. F. (2010). Multi-system neurological disease is common in patients with OPA1 mutations. Brain, 133, 771-786. https://doi.org/10.1093/brain/awq007
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. ; Duffey, P. ; Miller, J. ; Whittaker, R. G. ; Baker, M. R. ; Jackson, M. J. ; Clarke, M. P. ; Dhillon, B. ; Czermin, B. ; Stewart, J. D. ; Hudson, G. ; Reynier, P. ; Bonneau, D. ; Marques, W. ; Lenaers, G. ; McFarland, R. ; Taylor, R. W. ; Turnbull, D. M. ; Votruba, M. ; Zeviani, M. ; Carelli, V. ; Bindoff, L. A. ; Horvath, R. ; Amati-Bonneau, P. ; Chinnery, P. F. / Multi-system neurological disease is common in patients with OPA1 mutations. In: Brain. 2010 ; Vol. 133. pp. 771-786.
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abstract = "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 = "P. Yu-Wai-Man and Griffiths, {P. G.} and Gorman, {G. S.} and Lourenco, {C. M.} and Wright, {A. F.} and M. Auer-Grumbach and A. Toscano and O. Musumeci and Valentino, {M. L.} and L. Caporali and C. Lamperti and Tallaksen, {C. M.} and P. Duffey and J. Miller and Whittaker, {R. G.} and Baker, {M. R.} and Jackson, {M. J.} and Clarke, {M. P.} and B. Dhillon and B. Czermin and Stewart, {J. D.} and G. Hudson and P. Reynier and D. Bonneau and W. Marques and G. Lenaers and R. McFarland and Taylor, {R. W.} and Turnbull, {D. M.} and M. Votruba and M. Zeviani and V. Carelli and Bindoff, {L. A.} and R. Horvath and P. Amati-Bonneau and Chinnery, {P. F.}",
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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 2010, 'Multi-system neurological disease is common in patients with OPA1 mutations', Brain, vol. 133, pp. 771-786. https://doi.org/10.1093/brain/awq007

Multi-system neurological disease is common in patients with OPA1 mutations. / 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.; Duffey, P.; Miller, J.; Whittaker, R. G.; Baker, M. R.; Jackson, M. J.; Clarke, M. P.; Dhillon, B.; Czermin, B.; Stewart, J. D.; Hudson, G.; Reynier, P.; Bonneau, D.; Marques, W.; Lenaers, G.; McFarland, R.; Taylor, R. W.; Turnbull, D. M.; Votruba, M.; Zeviani, M.; Carelli, V.; Bindoff, L. A.; Horvath, R.; Amati-Bonneau, P.; Chinnery, P. F.

In: Brain, Vol. 133, 03.2010, p. 771-786.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multi-system neurological disease is common in patients with OPA1 mutations

AU - Yu-Wai-Man, P.

AU - Griffiths, P. G.

AU - Gorman, G. S.

AU - Lourenco, C. M.

AU - Wright, A. F.

AU - Auer-Grumbach, M.

AU - Toscano, A.

AU - Musumeci, O.

AU - Valentino, M. L.

AU - Caporali, L.

AU - Lamperti, C.

AU - Tallaksen, C. M.

AU - Duffey, P.

AU - Miller, J.

AU - Whittaker, R. G.

AU - Baker, M. R.

AU - Jackson, M. J.

AU - Clarke, M. P.

AU - Dhillon, B.

AU - Czermin, B.

AU - Stewart, J. D.

AU - Hudson, G.

AU - Reynier, P.

AU - Bonneau, D.

AU - Marques, W.

AU - Lenaers, G.

AU - McFarland, R.

AU - Taylor, R. W.

AU - Turnbull, D. M.

AU - Votruba, M.

AU - Zeviani, M.

AU - Carelli, V.

AU - Bindoff, L. A.

AU - Horvath, R.

AU - Amati-Bonneau, P.

AU - Chinnery, P. F.

PY - 2010/3

Y1 - 2010/3

N2 - 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.

AB - 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.

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DO - 10.1093/brain/awq007

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SP - 771

EP - 786

JO - Brain

JF - Brain

SN - 0006-8950

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Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133:771-786. https://doi.org/10.1093/brain/awq007