Elsevier

The Lancet

Volume 355, Issue 9200, 22 January 2000, Pages 299-304
The Lancet

Seminar
Mitochondrial respiratory chain disorders I: mitochondrial DNA defects

https://doi.org/10.1016/S0140-6736(99)05225-3Get rights and content

Summary

Mitochondria have a pivotal role in cell metabolism, being the major site of ATP production via oxidative phosphorylation (oxphos); they have a critical role in apoptotic cell death; and they also contribute to human genetics since mitochondria have a functional genome separate from that of nuclear DNA. Defects of mitochondrial metabolism are associated with a wide spectrum of disease. An important part of this spectrum is caused by mutations of mitochondrial DNA (mtDNA). These class I oxphos diseases are covered in part I of this two-part review. Dysfunction of mitochondrial oxphos has also emerged as an important component of a range of predominantly neurodegenerative diseases in which the mitochondrial abnormality is most probably secondary. These class II oxphos diseases are due to mutations of genes not encoding oxphos subunits or are caused by exogenous or endogenous oxphos toxins. Class II mitochondrial diseases and the mitochondrion's role in apoptosis are covered in part II (Lancet 2000; 355: 389–94).

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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