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The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO

The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO
The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO
Background: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)–deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease.
Methods: We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations.
Results: Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52%(17/33) reporting fatigue and33%(11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable
variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants.
Conclusions: Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.
0028-3878
1619-1626
Fratter, C.
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Gorman, G. S.
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Stewart, J. D.
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Buddles, M.
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Smith, C.
2019b8d8-ee85-40ff-9bb1-76916a21de6b
Evans, J.
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Seller, A.
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Poulton, J.
cb26ba47-f06f-46ae-865e-4ae78e31e323
Roberts, M.
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Hanna, M. G.
baf383d1-8982-48e9-b306-11583a93d00b
Rahman, S.
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Omer, S. E.
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Klopstock, T.
96d2dce9-54f8-4610-ba77-7a0e5291276e
Schoser, B.
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Kornblum, C.
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Czermin, B.
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Lecky, B.
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Blakely, E. L.
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Craig, K.
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Chinnery, P. F.
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Turnbull, D. M.
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Horvath, R.
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Taylor, R. W.
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Fratter, C.
a6186a6f-2afb-4ba4-818b-613ad22c0294
Gorman, G. S.
6e472154-d0b4-4e65-9453-fb787eb215b6
Stewart, J. D.
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Buddles, M.
802998d0-e5ba-4de4-b8e8-b2c48a5513ed
Smith, C.
2019b8d8-ee85-40ff-9bb1-76916a21de6b
Evans, J.
f551701f-0ce1-4816-8a77-5a87eaf721a3
Seller, A.
0a0cecb5-37a0-4a04-8aa9-6a31c274e236
Poulton, J.
cb26ba47-f06f-46ae-865e-4ae78e31e323
Roberts, M.
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Hanna, M. G.
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Rahman, S.
52ba60fa-ad08-4017-b92c-7b5625b598a7
Omer, S. E.
33ef6090-3090-4c20-bbee-01f53d3eac2c
Klopstock, T.
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Schoser, B.
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Kornblum, C.
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Czermin, B.
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Lecky, B.
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Blakely, E. L.
5e68ada6-062d-435a-b49e-1a063c2589ab
Craig, K.
dd2d7687-29f0-4889-b002-4b9faa20305f
Chinnery, P. F.
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Turnbull, D. M.
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Horvath, R.
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Taylor, R. W.
f108dcd2-408c-4290-a546-288f7600ed57

Fratter, C., Gorman, G. S., Stewart, J. D., Buddles, M., Smith, C., Evans, J., Seller, A., Poulton, J., Roberts, M., Hanna, M. G., Rahman, S., Omer, S. E., Klopstock, T., Schoser, B., Kornblum, C., Czermin, B., Lecky, B., Blakely, E. L., Craig, K., Chinnery, P. F., Turnbull, D. M., Horvath, R. and Taylor, R. W. (2010) The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology, 74 (20), 1619-1626. (doi:10.1212/WNL.0b013e3181df099f). (PMID:20479361)

Record type: Article

Abstract

Background: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)–deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease.
Methods: We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations.
Results: Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52%(17/33) reporting fatigue and33%(11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable
variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants.
Conclusions: Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.

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Published date: 2010
Organisations: Centre for Biological Sciences

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Local EPrints ID: 355897
URI: http://eprints.soton.ac.uk/id/eprint/355897
ISSN: 0028-3878
PURE UUID: a1d0021b-0bd6-465b-a2fa-f502e3fc2feb
ORCID for J. D. Stewart: ORCID iD orcid.org/0000-0002-2608-1967

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Date deposited: 04 Sep 2013 17:09
Last modified: 18 Feb 2021 17:20

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Contributors

Author: C. Fratter
Author: G. S. Gorman
Author: J. D. Stewart ORCID iD
Author: M. Buddles
Author: C. Smith
Author: J. Evans
Author: A. Seller
Author: J. Poulton
Author: M. Roberts
Author: M. G. Hanna
Author: S. Rahman
Author: S. E. Omer
Author: T. Klopstock
Author: B. Schoser
Author: C. Kornblum
Author: B. Czermin
Author: B. Lecky
Author: E. L. Blakely
Author: K. Craig
Author: P. F. Chinnery
Author: D. M. Turnbull
Author: R. Horvath
Author: R. W. Taylor

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