SeminarMitochondrial respiratory chain disorders I: mitochondrial DNA defects
Section snippets
Electron transport and oxphos
The core of the pathway is five multisubunit complexes (I–V) located on the inner mitochondrial membrane. Reducing equivalents (electrons) pass along the chain from various substrates, providing the energy to pump hydrogen ions (protons) across the inner membrane from the matrix side at complexes I, III, and IV. The electrochemical gradient of about 150 mV that is thus established drives ATP generation via complex V (ATPase). Different substrates are metabolised producing reducing equivalents
Clinical manifestations of mitochondrial disorders
A striking feature of mtDNA disorders is their clinical heterogeneity, ranging from single-organ involvement to severe multisystem disease. The same mutation or different mutations in the same mtDNA gene may present with very different clinical manifestations while the same clinical phenotype may be caused by different mutations. Some of the more common clinical phenotypes and mtDNA mutations are discussed below.
This variability in clinical manifestation may be due to several factors, including
Biochemistry
Blood lactate concentrations and lactate: pyruvate ratios may be increased at rest and rise significantly above those for matched controls after exercise. In patients with encephalopathy, particularly in infants, CSF lactate may be raised. Creatine kinase levels are either normal or only mildly increased. Renal tubular dysfunction may be seen as part of the Fanconi syndrome in Pearson's syndrome, kss, or melas.
Electrophysiology
The electromyogram is normal or only mildly myopathic while nerve conduction studies
Molecular genetics
Whilst muscle biopsy may prove diagnostic clinically, molecular genetic analysis is necessary for genetic counselling. mtDNA rearrangements are not usually found in blood whilst point mutations are; both types are seen in muscle. Thus a negative result for mutation analysis of mtDNA in blood does not exclude mitochondrial oxphos disease.
Single mtDNA deletion is the commonest mutation identified in patients presenting in adolescence or adulthood. These mutations are seen most frequently in cpeo
Treatment
At present there is no cure for disorders of mtDNA. Supportive management includes using bicarbonate and dialysis to correct severe lactic acidosis during episodes of decompensation. Seizures should be controlled with anticonvulsants but not phenobarbitone because it inhibits oxphos. Sodium valproate inhibits several pathways of intermediary metabolism and should be used with caution in patients with oxphos deficiencies. Strokes are managed in the usual way and patients should be investigated
Genetic counselling
Most patients with mtDNA mutations present as apparently sporadic cases. Patients with mtDNA deletions and cpeo or kss probably develop from ova in which somatic mutations have arisen de novo and deletions are rarely identified in maternal relatives. 40% of patients with the commonest LHON mutations (G11778A) have no family history of the disease.12 Nor do many patients with mtDNA tRNA mutations although close inquiry may reveal isolated deafness or diabetes. Thus, although a maternal history
Glossary of abbreviations
- cox
- Cytochrome oxidase
- cpeo
- Chronic progressive external ophthalmoplegia
- kss
- Kearns Sayre syndrome
- melas
- Myopathy, encephalopathy, lactic acidosis, stroke-like episodes
- merrf
- Myoclonic epilepsy with ragged red fibres
- narp
- Neurogenic weakness, ataxia, retinitis pigmentosa
- oxphos
- Oxidative phosphorylation
- sdh
- Succinate dehydrogenase
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