Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia

Progressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifesta...

Descripción completa

Detalles Bibliográficos
Autores principales: Horga, Alejandro, Pitceathly, Robert D. S., Blake, Julian C., Woodward, Catherine E., Zapater, Pedro, Fratter, Carl, Mudanohwo, Ese E., Plant, Gordon T., Houlden, Henry, Sweeney, Mary G., Hanna, Michael G., Reilly, Mary M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240292/
https://www.ncbi.nlm.nih.gov/pubmed/25281868
http://dx.doi.org/10.1093/brain/awu279
_version_ 1782345705249046528
author Horga, Alejandro
Pitceathly, Robert D. S.
Blake, Julian C.
Woodward, Catherine E.
Zapater, Pedro
Fratter, Carl
Mudanohwo, Ese E.
Plant, Gordon T.
Houlden, Henry
Sweeney, Mary G.
Hanna, Michael G.
Reilly, Mary M.
author_facet Horga, Alejandro
Pitceathly, Robert D. S.
Blake, Julian C.
Woodward, Catherine E.
Zapater, Pedro
Fratter, Carl
Mudanohwo, Ese E.
Plant, Gordon T.
Houlden, Henry
Sweeney, Mary G.
Hanna, Michael G.
Reilly, Mary M.
author_sort Horga, Alejandro
collection PubMed
description Progressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifestation of mitochondrial disease, although its prevalence and characteristics varies considerably among the different syndromes and genetic aetiologies. Based on clinical observations, we systematically investigated whether the presence of peripheral neuropathy could predict the underlying genetic defect in patients with progressive external ophthalmoplegia. We analysed detailed demographic, clinical and neurophysiological data from 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia. Seventy-eight patients (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA and 26 (22%) had mutations in either POLG, C10orf2 or RRM2B, or had multiple mitochondrial DNA deletions in muscle without an identified nuclear gene defect. Seventy-seven patients had neurophysiological studies; of these, 16 patients (21%) had a large-fibre peripheral neuropathy. The prevalence of peripheral neuropathy was significantly lower in patients with a single mitochondrial DNA deletion (2%) as compared to those with a point mutation of mitochondrial DNA or with a nuclear DNA defect (44% and 52%, respectively; P < 0.001). Univariate analyses revealed significant differences in the distribution of other clinical features between genotypes, including age at disease onset, gender, family history, progressive external ophthalmoplegia at clinical presentation, hearing loss, pigmentary retinopathy and extrapyramidal features. However, binomial logistic regression analysis identified peripheral neuropathy as the only independent predictor associated with a nuclear DNA defect (P = 0.002; odds ratio 8.43, 95% confidence interval 2.24–31.76). Multinomial logistic regression analysis identified peripheral neuropathy, family history and hearing loss as significant predictors of the genotype, and the same three variables showed the highest performance in genotype classification in a decision tree analysis. Of these variables, peripheral neuropathy had the highest specificity (91%), negative predictive value (83%) and positive likelihood ratio (5.87) for the diagnosis of a nuclear DNA defect. These results indicate that peripheral neuropathy is a rare finding in patients with single mitochondrial DNA deletions but that it is highly predictive of an underlying nuclear DNA defect. This observation may facilitate the development of diagnostic algorithms. We suggest that nuclear gene testing may enable a more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy.
format Online
Article
Text
id pubmed-4240292
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-42402922014-11-21 Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia Horga, Alejandro Pitceathly, Robert D. S. Blake, Julian C. Woodward, Catherine E. Zapater, Pedro Fratter, Carl Mudanohwo, Ese E. Plant, Gordon T. Houlden, Henry Sweeney, Mary G. Hanna, Michael G. Reilly, Mary M. Brain Original Articles Progressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifestation of mitochondrial disease, although its prevalence and characteristics varies considerably among the different syndromes and genetic aetiologies. Based on clinical observations, we systematically investigated whether the presence of peripheral neuropathy could predict the underlying genetic defect in patients with progressive external ophthalmoplegia. We analysed detailed demographic, clinical and neurophysiological data from 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia. Seventy-eight patients (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA and 26 (22%) had mutations in either POLG, C10orf2 or RRM2B, or had multiple mitochondrial DNA deletions in muscle without an identified nuclear gene defect. Seventy-seven patients had neurophysiological studies; of these, 16 patients (21%) had a large-fibre peripheral neuropathy. The prevalence of peripheral neuropathy was significantly lower in patients with a single mitochondrial DNA deletion (2%) as compared to those with a point mutation of mitochondrial DNA or with a nuclear DNA defect (44% and 52%, respectively; P < 0.001). Univariate analyses revealed significant differences in the distribution of other clinical features between genotypes, including age at disease onset, gender, family history, progressive external ophthalmoplegia at clinical presentation, hearing loss, pigmentary retinopathy and extrapyramidal features. However, binomial logistic regression analysis identified peripheral neuropathy as the only independent predictor associated with a nuclear DNA defect (P = 0.002; odds ratio 8.43, 95% confidence interval 2.24–31.76). Multinomial logistic regression analysis identified peripheral neuropathy, family history and hearing loss as significant predictors of the genotype, and the same three variables showed the highest performance in genotype classification in a decision tree analysis. Of these variables, peripheral neuropathy had the highest specificity (91%), negative predictive value (83%) and positive likelihood ratio (5.87) for the diagnosis of a nuclear DNA defect. These results indicate that peripheral neuropathy is a rare finding in patients with single mitochondrial DNA deletions but that it is highly predictive of an underlying nuclear DNA defect. This observation may facilitate the development of diagnostic algorithms. We suggest that nuclear gene testing may enable a more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy. Oxford University Press 2014-12 2014-10-04 /pmc/articles/PMC4240292/ /pubmed/25281868 http://dx.doi.org/10.1093/brain/awu279 Text en © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Horga, Alejandro
Pitceathly, Robert D. S.
Blake, Julian C.
Woodward, Catherine E.
Zapater, Pedro
Fratter, Carl
Mudanohwo, Ese E.
Plant, Gordon T.
Houlden, Henry
Sweeney, Mary G.
Hanna, Michael G.
Reilly, Mary M.
Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
title Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
title_full Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
title_fullStr Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
title_full_unstemmed Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
title_short Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
title_sort peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240292/
https://www.ncbi.nlm.nih.gov/pubmed/25281868
http://dx.doi.org/10.1093/brain/awu279
work_keys_str_mv AT horgaalejandro peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT pitceathlyrobertds peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT blakejulianc peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT woodwardcatherinee peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT zapaterpedro peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT frattercarl peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT mudanohwoesee peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT plantgordont peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT houldenhenry peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT sweeneymaryg peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT hannamichaelg peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia
AT reillymarym peripheralneuropathypredictsnucleargenedefectinpatientswithmitochondrialophthalmoplegia