116th ENMC international workshop: the treatment of mitochondrial disorders, 14th–16th March 2003, Naarden, The Netherlands

Article Outline

• 1. Introduction
• 2. Defining the extent of the problem: the epidemiology of mitochondrial disease
• 3. Measuring disease severity
  • 3.1. Intermediary metabolites
  • 3.2. Respiratory chain studies
  • 3.3. Muscle histochemistry
  • 3.4. Heteroplasmy
  • 3.5. Exercise testing and near infrared spectroscopy
  • 3.6. Magnetic resonance spectroscopy
  • 3.7. Clinical investigations
  • 3.8. Mitochondrial disease rating scale
• 4. Current best practice for the treatment of mitochondrial disorders
  • 4.1. Specific drug treatment and vitamin supplementation
    • 4.1.1. Dichloroacetate
    • 4.1.2. Co-enzyme Q10
    • 4.1.3. Nicotinamide
    • 4.1.4. Riboflavin
    • 4.1.5. Vitamin E
    • 4.1.6. Corticosteroids
    • 4.1.7. Other approaches
  • 4.2. Specific management issues
    • 4.2.1. Gastrointestinal and nutritional
    • 4.2.2. Cardiac complications
    • 4.2.3. Transplantation
    • 4.2.4. Hearing impairment
    • 4.2.5. Lifestyle issues—smoking and alcohol
    • 4.2.6. Effects of pregnancy
    • 4.2.7. Fatigue and muscle weakness
    • 4.2.8. Seizures and epilepsy
    • 4.2.9. Encephalopathy and stroke-like episodes
    • 4.2.10. Myoclonus
    • 4.2.11. Other neurological complications
    • 4.2.12. Ptosis and ophthalmoplegia
    • 4.2.13. Diabetes
    • 4.2.14. Indications and duration of ventilation in children with mitochondrial disease
    • 4.2.15. Other specific paediatric complications
• 5. Novel treatment approaches
• 6. Developing the European network and future proposals
• Acknowledgements
• appendix a. Participants
• appendix b. ENMC mitochondrial disease rating scale
  • B.1. Section 1: activities of daily living
  • B.2. Section 2: motor
  • B.3. Section 3: special sensory
  • B.4. Section 4: endocrine
  • B.5. Section 5: cardiac
  • B.6. Section 6: cognition and behaviour
• References
• Copyright

Keywords:  Mitochondrial disorders, Mitochondrial encephalomyopathy, Metabolic disease, Respiratory chain

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1. Introduction 

Twenty participants from Denmark, Finland, France, Germany, Italy, Norway, Sweden, The Netherlands, the UK, and the USA met to discuss the treatment of mitochondrial disorders in children and adults. The group included adult and paediatric neurologists, metabolic paediatricians, an ophthalmologist, an endocrinologist, and other clinical scientists. The aim of the workshop was to define the extent of the clinical problem (the epidemiology of mitochondrial disease), discuss methods of assessing disease severity that might be used to assess treatment response, discuss the current best practice for the treatment of mitochondrial disease, and explore novel treatment strategies. During the workshop, the participants discussed their own clinical experience of the management of mitochondrial disease and by the end of the workshop, the participants produced two documents which are included in this report:

The participants recognised clear differences in the clinical management of young children with encephalomyopathies or multi-organ failure and older children who often have a more chronic disease course similar to adult patients. Different strategies are needed to monitor disease severity and clinically manage these two groups. These differences are reflected in the different sections of this report.

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2. Defining the extent of the problem: the epidemiology of mitochondrial disease 

Although mitochondrial disorders are still relatively rare, as a group, they are much more common than previously thought. There have been population-based studies of mitochondrial disorders in children and adults. The incidence of mitochondrial encephalomyopathies in preschool children (<6 years of age) was 1/11,000 and the point prevalence of mitochondrial encephalomyopathies in children under 16 was 1/21,000 in western Sweden [1]. Similar figures were found in a different population in Victoria, Australia [2]. Mitochondrial DNA (mtDNA) mutations were uncommon in the affected children. Mitochondrial disorders affected 1/15,221 adults in the north east of England [3]. Most of the adults had pathogenic mtDNA mutations and the overall prevalence of pathogenic mtDNA mutations was 1/8012 in the same region, including affected and unaffected adults and children. When the results of these studies are combined, the overall figure for the prevalence of mitochondrial disorders is ∼1/8500 individuals [4]. The A3243G mtDNA mutation was found in 1/6134 individuals in northern Finland [5]. It is unclear whether this high incidence reflects a real difference between the study populations or the methods of ascertainment. These studies reflect the minimum prevalence of mitochondrial disease within the population and it is likely that the prevalence figures will increase as the genotypic and phenotypic spectrum of mitochondrial disorders broaden. Mitochondrial disorders are, therefore, much more common than was previously thought. This has clear implications for the allocation of health care resources and places even greater emphasis on developing new approaches to the clinical management of patients with mitochondrial disease.

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3. Measuring disease severity 

Mitochondrial disorders can affect many different organ systems and the pattern of clinical involvement varies greatly from individual to individual. This poses a particular challenge when trying to measure disease severity in such a heterogeneous group of patients. The participants discussed the advantages and disadvantages of conventional and novel techniques for measuring the severity of mitochondrial disease.

3.1. Intermediary metabolites 

Patients with mitochondrial disease often have raised intermediary metabolites (lactate, pyruvate, and alanine) which can be measured in blood, urine, and CSF. Most of the participants find it helpful to measure lactate when investigating patients with mitochondrial disease, but it was generally accepted that other measurements (e.g. pyruvate and alanine) rarely contributed to the diagnosis. Whilst the participants recognised that there was a broad correlation between disease severity and lactate levels in patients with encephalopathy, there was considerable variability [6]. Moreover, since the level of intermediary metabolites is only a surrogate marker of disease activity, they are unlikely to be useful in monitoring disease activity over long periods.

3.2. Respiratory chain studies 

There are a number of problems using traditional biochemical methods for measuring mitochondrial function—the most obvious being the inconsistencies between different laboratories. The French are currently carrying out a study to assess the variability between different laboratories and identify the reasons for this. Preliminary data show that subtle differences in techniques can have a profound effect on mitochondrial function measured in the laboratory. This study is on going and the results will be freely available on a web site (possibly by the end of 2003). It is well recognised that some patients with proven mitochondrial disease can have normal mitochondrial function measured in the laboratory and the level of respiratory chain activity is dependent upon the degree of fitness and muscle activity of the patient around the time of the biopsy. For these reasons, the participants agreed that biochemical analyses can only be reliably used as an aid to diagnosis and not for monitoring disease severity.

3.3. Muscle histochemistry 

Mitochondrial disorders are associated with a range of histological and histochemical abnormalities. Characteristic features include ‘ragged-red’ fibres (RRF) due to the focal accumulation of mitochondria in the sub-sarcolemmal region and cytochrome c oxidase (COX) negative fibres. However, RRF are seen in a number of different non-mitochondrial disorders (for example, inclusion body myositis) and the muscle of healthy athletes may contain fibres that contain many mitochondria and look similar to RRF. COX negative fibres accumulate with age, confounding the interpretation in older individuals. It was generally accepted that COX negative fibres are not seen in healthy children and up to 2% COX negative fibres are seen in the muscle of healthy elderly individuals, but there is no clear age cut-off and interpreting the muscle biopsy can be particularly difficult in middle-aged and elderly patients with mild symptoms and a few COX negative fibres. It was stressed that the biopsy should be interpreted in the clinical context. It was also noted that some patients with mitochondrial disease have fat droplets within and between the muscle fascicles, giving the muscle a dystrophic appearance [7].

3.4. Heteroplasmy 

Patients with mtDNA disorders often harbour a mixture of mutant and wild-type mtDNA (heteroplasmy). Large cohort studies have shown a relationship between the percentage level of mutant mtDNA in skeletal muscle [8] and other tissues [9] and the severity of mitochondrial disease, but the relationship is less clear for individual patients. There may be a number of confounding factors including the level of activity of the patient (which is related to the total number of mitochondria and the amount of mtDNA) and there is increasing evidence that the amount of wild-type mtDNA may be more important than the proportion of mutant and wild-type mtDNA. It was generally accepted that further studies are needed to understand the relationship between phenotype and the underlying genetic defect.

3.5. Exercise testing and near infrared spectroscopy 

Exercise testing is a useful non-invasive technique for diagnosis and monitoring of mitochondrial disease in adults with mitochondrial disease with a predominant muscle phenotype [10], [11]. This may prove to be particularly useful for monitoring the effects of training which is a potential treatment for some adults with mitochondrial myopathies [12]. Near infrared spectroscopy is less well established but shows promise for the non-invasive monitoring of patients with a myopathy [13]

3.6. Magnetic resonance spectroscopy 

Magnetic resonance spectroscopy (MRS) is a non-invasive method for assessing oxidative metabolism in patients with mitochondrial disease. Proton MRS can be used to measure lactate levels in brain and muscle and also measure N-acetylaspartate (NAA) which is a marker of neuronal loss/dysfunction in the brain. Phosphorus MRS can be used to measure the rate of ATP production in skeletal muscle and tissue bioenergetics in myocardium. There are some inconsistencies between in vivo MRS data and biochemical data in patients with mitochondrial disease [14]. These differences may be due to nuclear genetic effects, but they largely remain unexplained. MRS has shown that high doses of co-enzyme Q10 (400 mg/day), in association with vitamin E (2100 IU/day) are effective in patients with Friedreich's ataxia [15].

3.7. Clinical investigations 

Routine clinical investigations can be used to monitor specific phenotypes in patients with mitochondrial disease. For example, pure tone audiometry has been used to document the rate of hearing loss in patients with the A3243G mutation [16] and echocardiography in patients with A3243G [17]. Measurements of ophthalmoplegia and ptosis pose particular problems, but these can be overcome using relatively simple apparatus that is available in most ophthalmology departments (such as the Goldman perimeter to measure visual fields). There have been very few longitudinal clinical studies of patients with mitochondrial disease using clinical investigations. The participants stressed the importance of future prospective studies documenting the natural history of mitochondrial disease. These studies are essential to design adequately powered clinical trials for novel treatments.

3.8. Mitochondrial disease rating scale 

Designing a disease rating scale for mitochondrial disorders is particularly difficult because of the phenotypic heterogeneity. Specific phenotypes may be measured using conventional clinical tests and phenotype-specific rating scales that have already been validated. It may not be possible to develop a universal mitochondrial disease rating scale that reliably measures disease severity in all patient groups (for example, to compare childhood encephalopathy in Leigh syndrome and visual failure in Leber hereditary optic neuropathy). One approach is to sub-divide the phenotype into different groups and give a score for each area. This would allow each section to be used independently, whilst allowing a global score to be calculated if required. There was general agreement that the scale should be weighted towards activities of daily living and quality of life rather than physiological or pathological measurements. This would enable assessment of parameters that are actually important to patients rather than those that interest doctors and scientists. A draft rating scale was put together combining different components of established rating scales (including the unified Parkinson's disease rating scale (UPDRS), the International cooperative ataxia rating scale (ICARS), the Medical Research Council scale for muscle power, and the Medical Research Council scale for hearing impairment). This draft appears at the end of this report. One participant had developed a simple activity chart in an attempt to measure treatment related changes objectively using a scale tailored to the individual.

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4. Current best practice for the treatment of mitochondrial disorders 

Much of our experience of the treatment of mitochondrial disease is based upon anecdotal reports and small case series. These reports must be interpreted with great caution. We do not have a clear picture of the natural history of mitochondrial disorders and many of the reported clinical improvements may just reflect a fluctuating disease course rather than a real effect of treatment. The participants also recognised the importance of prospective longitudinal natural history studies which will form the foundation for future treatment trails.

4.1. Specific drug treatment and vitamin supplementation 

It was generally accepted that there is no clear evidence that dichloroacetate (DCA) has any effect other than to reduce lactic acid levels and limited data suggest that DCA may be associated with a poor outcome in some cases. Some of the participants use DCA for short periods (25 mg/kg/day) to reduce lactic acid levels in neonatal lactic acidosis and in patients with A3243G MELAS during encephalopathic episodes. DCA often causes significant side effects including a painful peripheral neuropathy.

There are anecdotal reports of clinical improvements on CoQ10 and positive results from a number of small open clinical trials (90–240 mg/day in divided doses). Although these treatments may improve surrogate markers of disease activity (e.g. lactate and pyruvate), no clear and sustained clinical improvement has been reported. Many of the participants give a therapeutic trial which is often stopped after 1–6 months because it has no effect. CoQ10 has been used in patients with Friedreich's ataxia (400 mg/day). Idebenone, a short chain quinone analogue, has been used in patients with Leber hereditary optic neuropathy (5 mg/kg/day). Some of the participants use idebenone in patients with mitochondrial disorders.

Some of the participants reported positive effects of nicotinamide (50–75 mg/kg/day) particularly in improving biochemical parameters. There is, however, no clear evidence that nicotinamide has a significant clinical effect and patients often report adverse effects during treatment.

There is a clear biochemical rationale for giving riboflavin to patients with complexes I or II deficiency, but no hard clinical data to support its use. Most of the participants would try between 10 and 100 mg of riboflavin daily for 6 months in patients with complex I deficiency before stopping the treatment if it is ineffective.

Vitamin E (50 μg/day) has been used alone or in combination with β-carotene (12.5 μg once per week) particularly in patients with complex III deficiency, but also in patients with complexes I and IV deficiency. The treatment is usually given for 6 months and then stopped if it is ineffective.

Only one participant uses corticosteroids for the treatment of mitochondrial disease. The majority never use steroids.

One strategy is to use a multivitamin preparation for 6 months and if this appears to be effective, then to try and elucidate which component is having the positive effect. Carnitine supplementation is used by some of the participants when muscle carnitine is low. There are theoretical reasons why vitamin C might be deleterious for mitochondrial function and it is not used by the participants. Vitamin B12 may be of use in mitochondrial nucleoside disorders (thymidine kinase, thymidine phosphorylase and deoxyguanosine kinase deficiencies) where it might modulate intra-mitochondrial nucleoside levels.

4.2. Specific management issues 

No specific treatments are being used for gastrointestinal hypo- or hypermotility or gastrointestinal pseudo-obstruction. Although most of the participants reported favourable results by managing pseudo-obstruction conservatively, at least one patient has died from intestinal perforation, so surgery may be required in some cases. One study has reported improved swallowing in patients with dysphagia following cricopharyngeal myotomy [18], but the participants stressed the importance of early gastrostomy in mitochondrial patients with weight loss and poor nutrition despite dietary intervention. Gastrostomy can have a major effect on the general well being of patients with mitochondrial disease. It is important to consider using total parenteral nutrition (TPN) and although TPN may precipitate acute liver failure in patients with liver dysfunction, this has not been seen by the participants. TPN may precipitate mitochondrial diabetes for the first time.

There are case reports of sudden death in patients with heart block, highlighting the importance of early cardiac pacing even in the absence of symptoms. No specific treatments have been used or avoided in patients with mitochondrial cardiomyopathies.

Provided that there are no major multi-system complications, the participants reported good results from cardiac (n=3) transplantation in mitochondrial disease. In a study of childhood cardiomyopathy, seven of 17 cases were considered to be suitable candidates for transplantation. Transplantation should be used more widely in the future. Liver and renal transplantations have been carried out, but much less frequently.

Patients often require a hearing aid. Some patients find that digital hearing aids are better than analogue hearing aids. Participants reported many instances where cochlear implantation has been successful.

Smoking should be avoided as part of general health care advice. The participants are not aware of any evidence that alcohol is detrimental for the majority of patients with mitochondrial disease.

Although there have been case reports of a deterioration of mitochondrial disease during pregnancy, the participants are aware of many pregnancies where there have been no complications. At present, there is no clear evidence that pregnancy leads to a deterioration of mitochondrial disease. It is more likely that clinical progression of mitochondrial disease makes pregnancy more difficult rather than a direct effect of the pregnancy on the disease itself.

These symptoms may respond to exercise therapy. This is being used by some of the participants, but there are concerns that the percentage level of mutant mtDNA may actually increase with exercise. CoQ10 may help with fatigue (90–240 mg/day in divided doses). Patients may develop nocturnal hypoventilation requiring non-invasive ventilation.

The participants treat seizures in the conventional way, but avoid using sodium valproate if possible. The most frequently used first line agents are carbamazepine and lamotrigine, although other agents have been used (e.g. levetiracetam). Second line agents include phenytoin, phenobarbitone, and topiramate in standard doses.

In patients with encephalopathy and stroke-like episodes, it is important to search for and treat infection, adequately hydrate a patient, and treat any seizures. Some of the participants look for sub-clinical epileptic activity on the electroencephalogram (EEG) and treat this aggressively with anticonvulsants. One participant uses anticonvulsants in all patients who have had a stroke-like episode and who have had either a seizure or paroxysmal discharges on EEG. Others only treat clinical seizures. If there is a high lactate level (pH 7.3 or below), some participants would use sodium bicarbonate or dichloroacetate (see above). There is no evidence that anti-platelet drugs prevent mitochondrial stroke-like episodes, but aspirin should be used in patients with mitochondrial diabetes who have evidence of atherosclerotic vascular disease.

Many patients with myoclonus do not need treatment. If treatment is required then clonazepam is the drug of choice.

Patients with mitochondrial disease may develop migraine, psychiatric disturbance, cognitive impairment, myalgia, neuropathic pain, ataxia, and spasticity. The participants manage these features as they would for non-mitochondrial patients with these problems. Triptans should be avoided in patients who have had a stroke-like episode or have an evolving stroke-like episode. There is currently no known treatment for visual failure.

Surgery for ptosis and ophthalmoplegia is technically difficult. The participants agreed that it should only be carried out by an ophthalmologist with a special interest in this area.

The variable clinical presentation, which can range between insulin dependence and non-insulin dependence, necessitates management on a case-by-case basis using conventional treatments.

It was recognised that the issues surrounding invasive ventilation will vary from patient to patient. In general, patients with suspected Leigh syndrome should be mechanically ventilated either because the diagnosis is uncertain (to give time for the diagnostic tests), to allow parents and relatives time to come to terms with the diagnosis and poor prognosis, or because the deterioration in respiratory function is associated with a recoverable illness (such as acute sepsis) . It is difficult to know when to withdraw ventilatory support. Children with infantile COX deficiency should be ventilated for 3–4 months because of the potential for late recovery of the myopathy. Some participants noted recovery in other Leigh syndrome patients after 4 weeks of ventilation, making it very difficult to withdraw ventilation within the first month unless there is generalised organ failure.

Problems such as sleep difficulties, over and under eating, and behavioural disturbance should be managed in the conventional way. Two participants have used melatonin (5 mg) to treat sleep disturbance. There was some concern about the use of growth hormone in treating growth delay because of recent reports of sudden death with this treatment in mitochondrial patients.

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5. Novel treatment approaches 

Various novel treatment strategies were discussed. Aerobic training has been shown to be of benefit in patients with mitochondrial myopathy [19], but there are concerns that the percentage level of mutant mtDNA may increase in skeletal muscle in some patients [12] and the long-term consequences of this treatment are not known. The participants currently recommend that patients maintain an average level of activity, making sure that they do not become de-conditioned or exercise vigorously. A more rigorous trial of the effects of aerobic exercise is planned for the near future.

Patients with a pure mitochondrial myopathy may benefit from ‘gene shifting’ procedures. Some patients with mitochondrial myopathies due to mtDNA defects have low levels of mutated mtDNA in skeletal muscle satellite cells. Satellite cell proliferation may be induced by myotoxins (for example, bupivacaine [20]) or eccentric exercise (lengthening contractions [21]). It is thought that the satellite cells fuse with the mature muscle fibres and deliver wild-type mtDNA to the affected fibres, reducing the overall proportion of mutant mtDNA to sub-threshold levels and correcting the biochemical phenotype. This is an experimental procedure at present.

A number of experimental treatments are currently under development. These include antigenomic agents directed against mutated mtDNA [22], allotopically expressed mitochondrial genes [23], [24], and nuclear transfer techniques. Patients with mtDNA depletion may benefit from drugs aimed at modifying intra-mitochondrial nucleoside levels.

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6. Developing the European network and future proposals 

The participants stressed the importance of the European collaboration to improve treatment for mitochondrial disease. It was agreed that the group should form an ENMC consortium and aim to meet again in 12–18 months to consolidate the links and compare prospectively collected natural history data and treatment experiences. Immediate aims would be to support a Cochrane review of the treatment of mitochondrial disease (ensuring that unpublished data is included) and develop an anonymous register of patients to facilitate collaboration between centres.

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Acknowledgements 

The workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and the main ENMC sponsors: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy); Muscular Dystrophy Campaign (UK), Musckelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schwiezerische Stifung für die Erforschung der Muskelkrankheiten (Switzerland), Osterreichische Muskelforschung (Austria), Vereniging Spierziekten Nederland (The Netherlands), and ENMC associate member: Muscular Dystrophy Association of Finland.

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appendix a. Participants 

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appendix b. ENMC mitochondrial disease rating scale 

B.1. Section 1: activities of daily living 

B.2. Section 2: motor 

B.3. Section 3: special sensory 

B.4. Section 4: endocrine 

For diabetes, add 1 for insulin treated

B.5. Section 5: cardiac 

B.6. Section 6: cognition and behaviour 

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