ReviewA neurological perspective on mitochondrial disease
Introduction
Over 20 years ago, Holt and colleagues1 reported the first association between a defect in mitochondrial DNA and human disease, and this was quickly followed later the same year by a second report from Wallace and colleagues.2 Since then, the number of disease-associated mitochondrial DNA mutations has expanded rapidly and mutations have been identified that cause classic mitochondrial syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy and ragged red fibres (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), Kearns-Sayre syndrome, and maternally inherited Leigh syndrome.3 The importance of nuclear genetic mutations in causing mitochondrial dysfunction and human disease has become increasingly clear over the past decade. Indeed, the putative role of mitochondrial respiratory chain deficiency in the pathogenesis of a wide range of neurological disorders has been the subject of intense scientific scrutiny.4, 5, 6, 7 In this Review, we discuss mitochondrial respiratory chain disease in the context of clinical neurology, providing an overview of not only the neurological aspects but also the multisystem effects of mitochondrial disease that neurologists must consider in both children and adults with this disorder. The genetic aetiology of mitochondrial disease has a substantial effect on the investigations requested by treating physicians and the type of counselling that is provided to families. We have therefore discussed the underlying genetics in depth, along with diagnostic and management strategies.
Mitochondria undertake many vital metabolic functions, probably the most important of which is oxidative phosphorylation, the principal method for generating ATP.3 This process is dependent on five intramembrane complexes and two mobile electron carriers (coenzyme Q10 and cytochrome c), which transport electrons between them. Supercomplexes (ie, respirasomes) are combinations of two or more respiratory chain complexes that can further enhance electron transfer. Although their role in the in-vivo action of the human mitochondrial respiratory chain remains contentious, evidence in favour of a multimeric organisation is accumulating.8
An interesting legacy of the primeval origins of mitochondria9 is the persistence of a 16·6 kb, double-stranded circle of DNA (mitochondrial DNA). This semi-autonomous genome encodes 13 structural subunit polypeptides and the machinery (22 transfer RNA molecules and 2 ribosomal RNA molecules) necessary for intramitochondrial protein synthesis.10 Mitochondrial DNA is present in multiple copies, and in any single cell a small number of these genomes might contain mutations; however, the proportion of mutated DNA is usually so small that for practical purposes the tissue can be regarded as homoplasmic (genetically uniform). By contrast, for several mitochondrial DNA mutations, tissue variation in the level of heteroplasmy (the existence of two or more distinct mitochondrial genomes at high concentrations within the same tissue) has a direct effect on the resultant phenotype and even small decreases in the concentrations of wild-type mitochondrial DNA might be sufficient to cause disease.11 However, the variable or single organ phenotypes that occur with homoplasmic mutations12, 13 and the apparent dominant nature of some mitochondrial transfer RNA (mitochondrial tRNA) mutations14 suggest that other, as yet undefined, factors are also important in determining the phenotype. Although nuclear genetic mutations causing mitochondrial dysfunction have been associated with several so-called new clinical phenotypes, some nuclear gene mutations can result in clinical phenotypes that are similar to those in primary mitochondrial DNA disease and the distinction between the two is not always clinically obvious.15
Section snippets
Prevalence of mitochondrial disease
Recent estimates of prevalence suggest that mitochondrial disease is more common than previously thought. Both the mitochondrial tRNA mutations MTTL1, m.3243A>G and MTRNR1, m.1555A>G (aminoglycoside-induced deafness) have frequencies of up to 1 in 400 in the general population,16, 17, 18 but many patients with these mutations remain asymptomatic. Clinical prevalence studies report that mitochondrial disease caused by mutations in mitochondrial DNA affects 9·2 in 100 000 adults aged less than 65
Point mutations of mitochondrial DNA
Novel point mutations in mitochondrial DNA are still being identified by use of high-throughput sequencing technology, some 22 years after the first mutation was identified.2 Most mitochondrial DNA mutations occur in a few families worldwide, but some, such as those that cause Leber's hereditary optic neuropathy (LHON), and the m.3243A>G mutation (in the MTTL1 gene), account for a large proportion of cases of mitochondrial disease. A disproportionately large number of these point mutations
Clinical evidence
The clinical presentation of mitochondrial disease is varied and can occur at almost any stage of life, often with involvement of an unusual combination of organs.3 Multisystem involvement in adult patients commonly occurs in the so-called classic mitochondrial syndromes, but, with the exception of Alpers-Huttenlocher syndrome (AHS) and Leigh syndrome, these classic syndromes are less common in young children with mitochondrial disease.65 A detailed family history can be informative, although
Baseline assessment
In view of the progressive, often multisystem, nature of mitochondrial disease, the health needs of all patients should be assessed in detail at the time of diagnosis and at regular intervals thereafter. We have developed and validated paediatric and adult clinical disease-rating scales specifically for this purpose.66, 67 Basic data relating to weight, height, and body-mass index should be recorded at each clinic visit, and in children this data should be plotted on appropriate growth charts.95
Specific treatment of mitochondrial disease
No specific pharmaceutical drugs have been clearly shown in large-scale clinical trials to treat mitochondrial disease effectively.99 However, there are anecdotal reports of improvement in fatigue and relief of myalgia associated with use of coenzyme Q10 and its analogue idebenone.100 In patients with coenzyme Q10 deficiency, coenzyme Q10 replacement therapy can also be beneficial but requires much higher doses.71 Riboflavin is also effective in some patients with complex I deficiency.101 Some
Conclusions
In a previous review,3 we concluded that nuclear–mitochondrial interaction must be important in the expression of mitochondrial disease and suggested that we were edging towards effective therapy. Although research now supports the first of these conjectures, we remain somewhat short of the mark on the latter. Nevertheless, with the development of national cohorts and registries, the potential for doing systematic large-scale studies of possible treatments is slowly becoming a reality. In
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