GENERAL INTRODUCTION
Mitochondria are responsible for converting food into energy within human cells. There are a number of genetically determined abnormalities of mitochondria that cause human diseases. These diseases usually involve organs that are heavily dependent upon the energy produced by mitochondria such as the brain, peripheral nerves, limb muscles, heart and hormone‐producing glands. As a result, mitochondrial disorders can cause muscle weakness on its own , but this is often associated with neurological, heart and hormone problems including diabetes. There is currently no established treatment for mitochondrial disorders, but there have been a number of case reports and small trials describing the positive effects of a number of different drugs, vitamins and food supplements. Exercise therapy has also been shown to help with the muscle symptoms. The purpose of this review is to assess objectively the available evidence for the various treatments that have been tried in mitochondrial myopathy.

MITOCHONDRIA AND HUMAN DISEASE
Mitochondrial disorders are a diverse group of conditions that often involve the nervous system, are usually progressive, and often cause significant disability and premature death (Leonard 2000; DiMauro 2001). Based upon recent epidemiological studies, mitochondrial disorders affect at least 1 in 8000 of the general population (Chinnery 2000; Darin 2001).

MITOCHONDRIAL FUNCTION AND BIOGENESIS
Mitochondria are complex ubiquitous intracellular organelles that perform an essential role in a number of cellular processes (Wallace 1999). They contain enzymes involved in cellular metabolism, and they may also be involved in programmed cell death (apoptosis). Mitochondria also play a pivotal role in the final common pathway of aerobic metabolism ‐ oxidative phosphorylation (OXPHOS). Oxidative phosphorylation is carried out by the mitochondrial respiratory chain, which is a group of five multi‐subunit enzyme complexes situated on the inner mitochondrial membrane that generate adenosine triphosphate (ATP) from intermediary metabolites. Adenosine triphosphate is a high‐energy phosphate molecule that provides an energy source for all active cellular processes. The term 'mitochondrial disorders' usually refers to primary disorders of the mitochondrial respiratory chain.

MOLECULAR PATHOLOGY OF MITOCHONDRIAL DISORDERS
The last ten years have seen major advances in our understanding of the biochemical and molecular basis of mitochondrial disease. The respiratory chain has a dual genetic basis (DiMauro 1998). The vast majority of the respiratory chain subunits (>70) are the products of nuclear genes. These subunits are synthesised within the cytosol and are delivered into mitochondria by a peptide targeting sequence. By contrast, thirteen essential respiratory chain subunits are synthesised within the mitochondrial matrix from small 16.5 kb circles of double‐stranded DNA called mitochondrial DNA (mtDNA) (Anderson 1981). Mitochondrial DNA is different to nuclear DNA in a number of respects. First, there are many thousands of copies of mtDNA within each cell. Mitochondrial DNA mutations may only affect a proportion of the mtDNA molecules, leading to a mixture of mutant and wild‐type mtDNA within the cell (heteroplasmy) (Holt 1988). Single cell studies have shown that the proportion of mutant mtDNA must exceed a critical threshold level before the cell expresses a biochemical defect of the mitochondrial respiratory chain (Schon 1997). This threshold varies from tissue to tissue, and partly explains the tissue‐selectivity seen in mitochondrial disorders (Wallace 1994). The percentage level of mutant mtDNA can also vary between and within individuals harbouring a pathogenic mtDNA defect, and this partly explains the clinical variability that is a hallmark of mtDNA disorders (Macmillan 1993).

CLINICAL FEATURES OF MITOCHONDRIAL DISEASES
Mitochondrial disorders principally affect tissues that are heavily dependent upon oxidative metabolism. These tissues include the central nervous system, peripheral nerves, eye, skeletal and cardiac muscle, and endocrine organs. Many individuals with mitochondrial respiratory chain disease have a multi‐system disorder that often involves skeletal muscle and the central nervous system, but some individuals have a disorder that only affects one organ system (Leonard 2000; DiMauro 2001). In general terms, the clinical features of mitochondrial disease can be divided into two groups: central neurological features (including encephalopathy, stroke‐like episodes, seizures, dementia and ataxia), and peripheral neurological features (including myopathy, ophthalmoplegia, and peripheral neuropathy). Some individuals have a mixture of central and peripheral features, whereas others have a pure central or peripheral phenotype. This distinction is important because the clinical management of central and peripheral features is different. They will therefore be considered separately in two independent Cochrane systematic reviews.

Many individuals with mitochondrial disease have a clearly defined clinical phenotype (summarised in Table 1). Chronic Progressive External Ophthalmoplegia (CPEO), the Kearns‐Sayre syndrome (KSS) and Pearson syndrome are usually due to a deletion of mtDNA (Zeviani 1988; Moraes 1989). Leber hereditary optic neuropathy (LHON), Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke‐like episodes (MELAS), Myoclonic Epilepsy with Ragged‐Red Fibres (MERRF), Maternally Inherited Diabetes and Deafness (MIDD), and Neurogenetic Ataxia with Retinitis Pigmentosa (NARP) are usually due to point mutations of mtDNA (Lamantea 2002). Unlike nuclear DNA, mtDNA is inherited down the maternal line, so these disorders either affect sporadic cases or they are passed from mother to child (Chinnery 1998). Children presenting with a relapsing encephalopathy with prominent brain stem signs and lactic acidosis (Leigh syndrome) may have a mtDNA defect, or an underlying nuclear genetic defect causing a respiratory chain deficiency. These mutations can affect the genes that code for the subunits themselves (complexes I and II) or genes important for the assembly of an intact respiratory chain (complexes III and IV) and they are usually autosomal recessive (Dahl 1998; Thorburn 2001).

A further group of mitochondrial disorders have recently been defined at the molecular level. These disorders result from a disorder of mtDNA maintenance. For some of these diseases the primary defect is an abnormality of the intra‐mitochondrial nucleoside pool. Most individuals with autosomal dominant PEO have a mutation in one of three genes: C10Orf2, Ant1 or POLG, which lead to the formation of multiple mtDNA deletions in muscle (Kaukonen 2000; Spelbrink 2001;Van Goethem 2001). Children presenting with mtDNA depletion syndrome may have mutations in the nuclear genes Thymidine kinase 2 (TK2) in the myopathic form, or Deoxyguanosine kinase (dGK) in the hepatic form (Mandel 2001; Saada 2001). Secondary mtDNA multiple deletions is also a feature of Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) which is also due to a disturbance of the intra‐mitochondrial nucleoside pool secondary to thymidine phosphorylase (TP) deficiency (Nishino 1999). A final important group are the disorders associated with co‐enzyme Q10 (ubiquinone) deficiency. This may present with childhood encephalopathy and seizures, recurrent rhabdomyolysis or ataxia with seizures. Case reports suggest that this disorder responds to Q10 replacement therapy (Musumeci 2001).

A large proportion of individuals with mitochondrial disease do not have a clearly defined phenotype. There may be single or multi‐organ involvement including the heart, endocrine organs (particularly the pancreas), and the nervous system. Gastrointestinal complications are an under recognised but common feature of mitochondrial disorders. Mitochondrial disease should be considered in any patient presenting with an unexplained progressive multi‐system disorder with prominent neurological features (Chinnery 1997).

SECONDARY MITOCHONDRIAL DISORDERS
Many other genetic disorders are also associated with abnormal mitochondrial function either as a secondary phenomenon, or because mitochondria play a crucial role in the pathophysiology of the disorder. To date these include three X‐linked conditions (Barth syndrome, sideroblastic anaemia with ataxia, deafness and dystonia DDP1) and a number of autosomal recessive (Friedreich's ataxia, spastic paraparesis SPG4 and SPG13, Wilson's disease) and autosomal dominant conditions (optic atrophy OPA1, hereditary paragangliomas). These disorders will not be considered in this Cochrane review.

CLINICAL MANAGEMENT OF MITOCHONDRIAL DISEASE
There is currently no established treatment for mitochondrial disorders, and the clinical management of individuals is largely supportive. The aims are to provide prognostic and genetic counselling.

Treatments used to modify the underlying disease process fall into three groups: pharmacological and nutritional agents, modification of macronutrient composition in the diet and exercise therapy. A number of different pharmacological treatments and nutritional supplements have been used in individuals with mitochondrial disease, with varying reports of success. These include antioxidants (co‐enzyme Q10, idebenone, vitamin C, vitamin E and menadione), agents that specifically improve lactic acidosis (dichloracetate), agents that correct secondary biochemical deficiencies (carnitine, creatine), respiratory chain co‐factors (nicotinamide, thiamine, riboflavin, succinate, and co‐enzyme Q10), and hormones (growth hormone and corticosteroids) (reviewed in Chinnery 2001). Much of the evidence used to support specific treatments comes from single case reports, but there have been a number of small quasi‐randomised trials and open‐labelled case series. Improvements following dietary modification (for example, a ketogenic diet) and exercise therapy (for example, endurance training) have also been documented in individual cases, and open‐labelled trials.

Assessing the efficacy of treatment is difficult for a number of reasons. First, the complex and variable phenotypes make it difficult to compare two or more individuals. Second, many mitochondrial disorders affect multiple organ systems which are difficult to compare (for example, it is difficult to compare an improvement in diabetic control with a reduction in seizure frequency). Thirdly, there is a lack of natural history data on individuals with mitochondrial disease. Finally, and partly because of these problems, there is no recognised disease rating scale for mitochondrial disorders to aid a comparison between different groups of individuals subjected to different treatments.

NOVEL TREATMENT STRATEGIES
A number of groups are developing treatments that act on the genetic level, but it is unlikely that these will be available for individuals in the near future (Taylor 2000; Chinnery 2001) . The aim of this review is to critically appraise the available evidence from randomised controlled trials for currently available treatments for individuals with mitochondrial disorders with peripheral neurological features.