University of Oulu

Myopathy and peripheral neuropathy associated with the 3243A>G mutation in mitochondrial DNA

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Author: Kärppä, Mikko1
Organizations: 1University of Oulu, Faculty of Medicine, Department of Neurology
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
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Language: English
Published: 2004
Publish Date: 2004-03-19
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium 8 of Oulu University Hospital, on May 19th, 2004, at 12 noon.
Reviewer: Professor Laurence Bindoff
Docent Bjarne Udd


Neurological features are common in mitochondrial diseases because tissues depending upon oxidative phosphorylation bear the brunt of the pathogenesis. The 3243A>G mutation in the MTTL1 gene in mitochondrial DNA is regarded as the most frequent mitchondrial point mutation and classically presents with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Myopathy and peripheral neuropathy have been documented in patients with mitochondrial diseases, but not properly characterised in patients with the 3243A>G mutation. We have previously determined the prevalence of patients with this mutation in a defined population in northern Finland.

The clinical spectrum and molecular aspects of myopathy and peripheral neuropathy are analysed here in a population-based cohort of patients with 3243A>G. Fifty patients were examined neurologically in order to define the frequency of myopathy and its histological, ultrastructural and clinical features. The frequency and phenotypic variability of peripheral neuropathy were determined in 32 patients and muscle computed tomography findings recorded in 24 patients. Finally, variations in mutation heteroplasmy were analysed in 10 patients using single muscle fibre PCR analysis.

The frequency of peripheral neuropathy was 22% (95% confidence interval (CI), 9–40%) and that of clinical myopathy 50% (95% CI, 36–64%). Moderate limb weakness was the most common myopathic feature, but mild weakness and external ophthalmoplegia were also present. CT scans revealed myopathic changes in 54% of the patients (95% CI, 33–76%), most frequently in the pelvic muscles. The incidence of myopathy was highest in the fifth decade of life, and higher age and male gender increased the risk of neuropathy. Muscle histology was abnormal in 72% of the cases examined (95% CI, 55–86%). The presence of intramitochondrial crystals and COX-negative fibres and variations in the size and shape of mitochondria were more common in the muscle of myopathic patients. Single muscle fibre analysis pointed to a correlation between the mutation load in ragged red fibres and in adjacent histologically normal fibres, and the proportion of 3243A>G in histologically normal muscle fibres showed a pattern compatible with random genetic drift.

The results indicate that myopathy and peripheral neuropathy are common in patients with the 3243A>G and that myopathy is highly variable in presentation. Segregation of 3243A>G in individual muscle fibres showed a complex process with random and non-random elements.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-7364-8
ISBN Print: 951-42-7363-X
Issue: 787
Copyright information: © University of Oulu, 2004. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.