title: Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia.
abstract: 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.
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK a.horga@ucl.ac.uk.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Horga
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.affiliation: 2 Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, NR4 7UY, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Blake
authors.affiliation: 3 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Woodward
authors.affiliation: 4 Clinical Pharmacology Section, Hospital General Universitario, Alicante, 03010, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Zapater
authors.affiliation: 5 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Fratter
authors.affiliation: 3 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Ese E
authors.initials: EE
authors.lastname: Mudanohwo
authors.affiliation: 6 National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Gordon T
authors.initials: GT
authors.lastname: Plant
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: 3 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D000293:Adolescent; D000328:Adult; D002467:Cell Nucleus / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial
keywords: POLG; mitochondrial DNA; mitochondrial DNA deletion; peripheral neuropathy; progressive external ophthalmoplegia