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Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people
  1. John Aaron Goodfellow1,
  2. Krishna Dani1,
  3. Willie Stewart2,
  4. Celestine Santosh3,
  5. John McLean4,
  6. Sharon Mulhern5,
  7. Saif Razvi1
  1. 1Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
  2. 2Department of Neuropathology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
  3. 3Department of Neuroradiology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
  4. 4Department of Clinical Physics and Biotechnology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
  5. 5Department of Neuropsychology, Ayrshire Central Hospital, Irvine, UK
  1. Correspondence to Dr John Aaron Goodfellow, Institute of Neurological Sciences, Department of Neurology, Southern General Hospital, 1345 Govan Road, Glasgow, G51 4TF; jagoodfellow{at}doctors.org.uk

Abstract

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes is a progressive, multisystem mitochondrial disease affecting children and young adults. Patients acquire disability through stroke-like episodes and have an increased mortality. Eighty per cent of cases have the mitochondrial mutation m.3243A>G which is linked to respiratory transport chain dysfunction and oxidative stress in energy demanding organs, particularly muscle and brain. It typically presents with seizures, headaches and acute neurological deficits mimicking stroke. It is an important differential in patients presenting with stroke, seizures, or suspected central nervous system infection or vasculitis. Investigations should exclude other aetiologies and include neuroimaging and cerebrospinal fluid analysis. Mutation analysis can be performed on urine samples. There is no high quality evidence to support the use of any of the agents reported in small studies. This article summarises the core clinical, biochemical, radiological and genetic features and discusses the evidence for a number of potential therapies.

http://dx.doi.org/10.1136/postgradmedj-2011-130326

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    Introduction

    Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is an uncommon metabolic disease that usually presents with seizures and stroke-like episodes in young people.1 2 Several causative mitochondrial DNA mutations have been demonstrated, the most common being m.3243A>G, and these are linked with dysfunction in the respiratory transport chain.3 4 It is a prototypical mitochondrial disorder in that it exhibits a maternal pattern of inheritance, variable proportion of mutated mitochondria in different tissues and over time (heteroplasmy) it affects tissues of high metabolic demand (brain, muscle), and a given tissue appears to require a certain level of affected mitochondria before clinical symptoms occur (the threshold effect). These factors contribute to the clinical heterogeneity of the disorder and the difficulty in diagnosis. An emerging concept is of juvenile- and adult-onset forms with the former more commonly having short stature and having a more initially severe and rapidly deteriorating course and the latter more commonly having cortical blindness, hearing loss and diabetes.5 Investigation is aimed at excluding other causes of seizures and stroke in young people and on confirming the mitochondrial cause. This typically requires urgent CT brain imaging, MRI (including MR spectroscopy (MRS)) and cerebrospinal fluid analysis. Urine testing is emerging as a preferred test for the mitochondrial mutation but muscle biopsy is still used in cases without recognised mutations to demonstrate the characteristic pathological changes of a mitochondrial cytopathy. Treatment remains purely supportive despite the plethora of compounds reported in small studies and case reports as potential therapies. Coenzyme Q10 (Q10) is often trialled in MELAS patients long term but without high-quality evidence to support it. In this article we review the clinical, radiological, metabolic, pathological and genetic features of this disease and summarise the data on the more commonly used therapeutic compounds.

    Clinical features

    In 1984, Pavlakis and colleagues described a distinct clinical syndrome in three of their own patients and from eight others in the medical literature.1 These patients had in common key clinical, biochemical, radiological and histological findings that allowed them to be distinguished from two other similar mitochondrial diseases, namely Kearns-Sayre syndrome (KSS) and myoclonic epilepsy with ragged-red fibres (MERRF). All three conditions have ragged-red fibres on muscle biopsy, a pathological hallmark of mitochondrial disease. The authors sought to delineate the distinct features of their patients. They derived the acronym MELAS from the major features: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.

    Hirano and Pavlakis later reviewed 110 cases in order to define the clinical spectrum;2 however, the core features in their original report remain the essentials of diagnosis and are the ‘classic’ features. The core clinical features of MELAS they described were: normal early development, short stature (also seen in MERRF and KSS), seizures (seen in MERRF but less in KSS), hearing loss (seen in MERRF and KSS) and stroke-like episodes which typically improve or fluctuate (usually cortical blindness, hemianopia, hemiparesis; not seen in MERRF and KSS). Thus, MELAS has both non-specific clinical findings common to other mitochondrial diseases and distinct, typical, focal neurological deficits.

    As in the original description, MELAS patients often present acutely with a febrile illness (eg, episodic headaches or vomiting) and focal neurological deficits and seizures with a background history of sensorineural deafness, cataracts or other features consistent with a mitochondrial disorder. The background features may be mild and not previously disclosed or investigated. Often the initial diagnosis is of stroke, vasculitis, encephalitis or migraine.2–4 Seizures are an almost universal feature of MELAS during the stroke-like episodes and subclinical seizures are thought to contribute to disease progression.

    Numerous other features have been reported in MELAS patients (such as type 2 diabetes mellitus) many of which are likely linked to the pathological mutation but due to variation in mutation, heteroplasmy and other factors these are not seen in every case. Table 1 summarises some of the commoner or more important clinical features, including their frequencies as determined in a number of studies.

    View this table:
    Table 1

    Clinical features seen in MELAS patients

    Although initially reported in the paediatric population and generally considered a condition with onset in the first or second decade, an emerging concept is of juvenile- and adult-onset forms.5 By this understanding the juvenile-onset cases are seen as presenting with more severe neurological impairments and with a more rapid decline and earlier mortality (median age from onset to death 6.4 in juvenile compared with 10.2 in adult-onset). It is proposed that there are differences in the clinical phenotypes in these two groups with the juvenile cases more commonly having short stature and the adult-onset form more commonly having cortical blindness, hearing loss and diabetes. These differences are postulated to reflect a greater initial burden of dysfunctional mitochondria in the juvenile-onset cases, leading to a more pronounced pathological phenotype at an earlier age.

    Radiological features

    In the original cases, CT imaging revealed changes consistent with cerebral infarction. CT is of limited value in demonstrating the brain lesions in MELAS but is often performed as it is widely available and indicated in the acute presentations of seizures, fever and stroke-like neurological deficits commonly seen in MELAS patients. There are no pathognomic features on CT, but there may be areas of focal infarction or bilateral basal ganglia calcifications.2 7 Usually basal ganglia calcifications are seen in older individuals and are idiopathic but in young individuals it should not be dismissed as idiopathic and every effort must be made to find an aetiology (figure 1). CT angiography is often also performed because of the clinical suspicion of large or medium vessel vasculitis.7

    Figure 1
    Figure 1

    CT findings in mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS). Plain CT in a 24-year-old woman presenting with fever, hemianopia and left face, arm, trunk and leg pain eventually diagnosed with MELAS. It shows non-specific calcification in the basal ganglia. This is uncommon in this age group but is a commonly reported finding in MELAS.

    MRI is now the cornerstone of diagnosis along with muscle biopsy and genetic studies. Although again there are no pathognomic features, the migrating lesions, which are not restricted to distinct arterial territories, strongly suggest a metabolic or mitochondrial disorder, rather than arterial occlusion. Serial MRI typically reveals lesions that are not restricted to arterial territories and migrate over time (figure 2). Commonly, the lesions affect the occipital and parietal lobes.8 The deep grey matter such as the thalamus may also be affected probably reflecting its high metabolic demand. On MRI the cortical lesions preferentially affect the cortical ribbon with relative sparing of the deeper white matter9 (figure 3), again reflecting the higher metabolic demand of these regions. Early reports argued that MELAS patients showed normal or increased apparent diffusion coefficient (ADC) on MRI;10 however, this has proven controversial and the consensus is probably now that there is restricted diffusion and so reduced ADC, as in ischaemic stroke.11 It is unclear exactly what pathophysiological process underlies the cerebrovascular dysfunction during stroke-like episodes but angiography usually does not show any stenosis or emboli12 and neither did the CT angiography done in our case reported in box 1. There are also data showing a heterogeneity of MRI findings in the acute setting, where cytotoxic oedema develops following a stroke-like episode and may overlap with hyper-perfusion and vasogenic oedema.13

    Figure 2
    Figure 2

    Typical migrating cortical and subcortical lesions on MRI in a mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episode (MELAS) patient (see box 1 for clinical details). Sequential MRIs taken on days (A) 11, (B) 19, (C) 26 and (D) 53 from onset of illness reveal the grey matter predilection and migrating nature of the lesions seen in MELAS.

    Figure 3
    Figure 3

    (A) Initial MRI in a mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode patient (1 week from onset of symptoms; see box 1 for clinical details). Lesions are seen in the right inferior parietal lobe, right medial occipital lobe, posterior aspects of both insular and posterior aspects of both temporal lobes. Several showed restricted diffusion and very mild localised swelling. MR venography revealed an increase in the number of small vessels in the abnormal regions. (B–D) MR spectroscopy. Multi-TE (echo time) acquisitions from region of the thalamus not acutely ischaemic (B) revealed characteristic lactate peak inversion between TE =144 ms (C) and 288 ms (D). This confirms the presence of elevated levels of lactate. Thin, horizontal lines show raw data and thick lines show modelled data.

    Box 1

    Case history

    A 24-year-old right-handed female supermarket worker presented with 3 days of nausea and vomiting and 1 day of severe, sudden-onset left face, arm, trunk and leg pain. Prior medical history included bilateral early cataracts, mild bilateral sensorineural hearing loss and 6 months of auditory hallucinations. No other psychiatric symptoms were reported. No family history of neurological illness was reported.

    On examination she was feverish (38.1°C), disorientated in place and time, had decreased attention, concentration and praxis, left–right disorientation, limited registration and limited insight. She had a left homonymous hemianopia, mild left hemiparesis, left hemi-sensory disturbance with allodynia and neuropathic pain.

    Biochemistry and haematology

    Inflammatory markers, haematological and biochemical indices were all normal except for a raised plasma lactate (5.4 mmol/l; normal range 0.8–2.4 mmol/l) and pyruvate (207 μmol/l; normal range 40–80 μmol/l). A CT brain revealed bilateral calcification of the globus pallidus (figure 1). Initial cerebrospinal fluid studies were normal.

    Imaging

    The initial brain imaging was a CT brain scan which showed bilateral symmetrical calcifications within the globus pallidi. MRI of the brain showed abnormalities within the right medial occipital lobes and right posterior hippocampus and these were of high signal on the T2 weighted scans. The occipital lesion involved the cortical grey and adjacent white matter. Similar high signal intensity lesions on the T2 weighted were also demonstrated within the right anterior temporal lobe and parts of both insular cortices (figure 3). Fluid attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) sequences also showed high signal whilst the ADC map showed subtly reduced signal in the cortical ribbon, consistent with cerebral ischaemia.

    Subsequent MRI brain scan 2 days later showed expansion of the right occipital lesion and extension into the right parietal lobe. All these lesions also showed restricted diffusion in keeping with ischaemia/infarctions.

    Follow-up MRI scan done a week later showed further expansion of the lesions into the right parietal lobe, right temporal lobe and into the right thalamus. There was regression of the abnormal signal change within the right insula. MR spectroscopy showed increased lactate within the abnormal area in the right thalamus but normal lactate spectrum from the normal right striatum (figure 3). Repeat cerebrospinal fluid analysis confirmed elevated lactate.

    A further follow-up MRI scan done a week later showed further regression of the abnormal changes within the right cerebral hemisphere, but it also showed further extension of abnormality into the right medial parietal lobe (see figure 2).

    The follow-up MRI scans done at 1 and 3 1/2 months after the initial MRI scan showed further regression of all the lesions with residual gliosis/oedema localised to the right temporal lobe and moderate enlargement of the right temporal and occipital horns due to local atrophy.

    Muscle biopsy

    A biopsy of the vastus lateralis muscle was performed. This muscle was selected as it is large and can usually be biopsied without significant risk of bleeding or nerve damage. It demonstrated increased droplet size, numerous ‘ragged-red’ fibres on Gomori trichrome, similar coarse staining in mitochondrial histochemistry and large numbers of fibres negative or pale stained for cytochrome oxidase (figure 4): appearances typical of a mitochondrial disorder. Subsequent genetic analysis of the muscle sample confirmed the recognised mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) mutation of m.3243A>G MTTL1 DNA at a high level of heteroplasmy.

    The patient's symptoms as with the imaging gradually improved with supportive management. After discharge from hospital, she developed frequent brief seizures. Electroencephalography demonstrated very frequent bursts of generalised poly-spike waves consistent with an idiopathic generalised epilepsy trait. She was started on levetiracetam. A trial of coenzyme Q was stopped due to the patient reporting side effects of gastrointestinal disturbance.

    She now has residual cognitive impairment which is a common feature in MELAS and typically progressive. Specifically she has marked impairment in visuospatial function, expressive language functioning, attention and executive function with relatively preserved praxis and some evidence of preserved encoding.

    Figure 4
    Figure 4

    Muscle biopsy sections from a mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode patient (see box 1 for clinical details). (A) H&E stain showing variation in fibre diameter. (B) Combined cytochrome oxidase and succinic dehydrogenase staining showing cytochrome oxidase-negative fibres (paler stained fibres) among normal fibres (darker). (C) Ragged-red fibres characteristic of mitochondrial cytopathies are present in the Gomori stain (darker staining, particularly around the edges of muscle fibres).

    MRS has emerged as a useful test in the workup of MELAS. MRS can prove useful in some circumstances as it offers a means of assessing, in vivo, brain metabolites. In the context of MELAS, it can confirm a higher than normal level of lactate in parts of the brain not acutely ischaemic, thereby confirming a level of metabolic derangement. It may also be accompanied by decreased N-acetylaspartate/N-acetylaspartatylglutamate.14 15 The presence of increased lactate (figure 3) points to an abnormality in the respiratory chain.16 Poorly functioning respiratory chains tend to be in an over-reduced state and increase production of reactive oxygen species. Glucose hypermetabolism may similarly over-reduce the respiratory transport chain. Oxidative stress and altered glucose metabolism have therefore been posed as pathological mechanisms for neuronal damage during acute episodes. Positron emission tomography imaging can evaluate regional cerebral blood flow, redox energy states and glucose metabolism in the living brain and have been used in research settings to further elucidate the pathogenesis of acute stroke-like lesions.17 The acute MELAS lesions appear to have an initial increase in blood flow and glucose metabolism and a degree of oxidative stress. In the subacute phase there is decreased blood flow and glucose use and increased oxidative stress. This then gives way to chronic decreased blood flow and glucose use and no evidence of oxidative stress (likely from neuronal death). This has led to the hypothesis that the lesions evolve as follows: neuronal hypermetabolism with increased energy demand; vasodilatation and hyperaemia leading to vasogenic oedema; oxygen overload and increased glucose metabolism; over-reduction of respiratory transport chains; increased reactive oxygen species generation (ie, oxidative stress); and neuronal cell damage.

    Metabolic and pathological features

    Plasma

    There are no pathognomic patterns of metabolic derangement on routine blood investigations. Elevated lactate indicates anaerobic metabolism and decreased N-acetylaspartate is strongly indicative of neuronal or axonal damage in the grey matter and is most marked in lesions during acute exacerbations.16 The impaired oxidative phosphorylation that underlies the neuronal dysfunction during exacerbations is caused by malfunction of the electron transport chain and reduced NAD+ and NADP+. This causes a switch to glycolytic metabolism within the cell and consequent increased production of lactate.

    Cerebrospinal fluid

    Lumbar puncture is usually performed as the presentation and imaging findings overlap with other neurological diseases, including encephalitis and vasculitis. Routine biochemical, virological and microbiological studies are usually normal. Pyruvate and lactate levels in the cerebrospinal fluid are usually increased, but this is not often performed initially if mitochondrial disease is not initially suspected.

    Muscle biopsy

    Muscle biopsy is a useful test to confirm a suspected mitochondrial disease.18 Typically, the vastus lateralis is used as it is large and biopsy is unlikely to cause major bleeding or nerve damage. Muscle also tends to retain higher levels of the mutation compared with blood, which can give false negatives. Urine-derived DNA testing is now available and is replacing muscle-derived DNA in clinical practice since the critical test in investigating mitochondrial disorders is to establish the genetic mutation rather than necessarily demonstrating muscle pathology.19 Nonetheless, muscle biopsy is useful in cases without recognised mutations or in the investigation of other mitochondrial disorders. There are well-established algorithms for the investigation of suspected mitochondrial diseases.20

    Ragged-red fibres

    Ragged-red fibres on Gomori stain are a hallmark of mitochondrial disease and are found in MELAS, MERRF and KSS. An irregular subsarcolemmal zone stains bright red as a consequence of the accumulation of abnormal mitochondria (figure 4). Oxidative enzyme stains will also mark these same fibres, thereby showing them to be metabolically active, in contradistinction to degenerating and regenerating myofibrils in other conditions.

    Neutral lipids

    Often, mitochondrial disorders will show an increase in neutral lipid staining within muscle fibres, which may be subtle.

    Glycogen

    Staining for glycogen with the periodic acid-Schiff reaction may identify excess glycogen in some mitochondrial diseases, especially in the ragged-red fibres.

    Oxidative enzymes

    A range of stains can be used to identify components of the respiratory chain. Nicotinamide adenine dinucleotide-tetrazolium reductase marks complex I and is found in the sarcoplasmic reticulum and mitochondria, succinic dehydrogenase (SDH) marks complex II and cytochrome oxidase marks complex IV/cytochrome c oxidase. Specific patterns suggest specific complex defects, for example, complex II defect can cause a complete absence of SDH staining; complex I, II, III or IV defects can cause absence of cytochrome oxidase staining but increased SDH staining; ragged-red fibres usually stain strongly for oxidative enzymes, in contrast to degenerating myofibres. This strong staining is thought to reflect an attempted compensatory proliferation of mitochondria.

    Electron microscopy

    Muscle biopsy specimens suggestive of MELAS may be investigated further with electron microscopy. In mitochondrial disorders electron microscopy usually reveals increased numbers, size and unusual morphologies of mitochondria. Often there are also abnormal granules or inclusions. Characteristically, there are also highly ordered crystal-like inclusions within the intermembrane spaces of the abnormal mitochondria: the so-called ‘railway-track’ or ‘parking lot’ inclusions.

    Respiratory transport chain

    It is possible to further localise the metabolic abnormality in MELAS patients using muscle homogenates and biochemical assays of enzyme function. Complexes II subunits are encoded by nuclear DNA while I, III and IV subunits are encoded in both nuclear and mitochondrial DNA. This is not routinely done for investigation of MELAS but is of considerable research interest as it may help identify key steps in the pathogenesis and may help target therapies.

    Genetics

    In the original MELAS report,1 the authors concluded from their clinical and pathological study that ‘The cause of these syndromes is uncertain. Presumably there is an underlying biochemical defect in mitochondria’, that there was ‘the possibility that MELAS is transmitted by non-Mendelian maternal inheritance’ and that ‘studies are in progress to determine whether the genetic aberration presumably associated with MELAS involves mitochondrial DNA’. These were astute insights and the authors did not have to wait long for confirmation of their hypotheses.

    In 1990, Goto and colleagues used direct sequencing and targeted PCR amplification techniques to identify a mutation in transfer RNA that was ‘specific but not exclusive to MELAS’ and which ‘seems to be the main cause of MELAS.’ They demonstrated an A to G point mutation in the transfer of RNALeu(UUR) gene at position 3243 of the mitochondrial genome in 26 of 31 MELAS patients that was present in only 1 of 29 patients with chronic progressive external ophthalmoplegia (another mitochondrial disease) and no MERRF or control patients.21 Sato and colleagues then went on in 1992 to confirm the maternal pattern of inheritance of the mutation in a number of pedigrees.22

    This mutation is now accepted to be present in around 80% of MELAS cases, 1% of type 2 diabetes mellitus and its frequency in the general population is around 1:150 00, making it a relatively common neurogenetic disease. Furthermore, prospective screening of neonates has revealed that up to 1 in 200 newborns harbour one of the commoner 10 mitochondrial mutations.23 24 It should be emphasised that overall only a small proportion of individuals with the m.3243A>G mutation will have any clinical symptoms. It occurs in the mitochondrial genome and as such is maternally inherited via the oocyte. Each mitochondrion has many copies of the mitochondrial genome, but each copy within a given cell is not always the same: the so-called heteroplasmy. This leads to variable penetrance and huge variation in clinical expression of a given genotype. Cell types and tissues within an individual vary in the proportion of abnormal mitochondrial DNA and a given tissue can have different levels over time,25 further complicating interpretation of genetic investigation and analysis. A host of other mutations have also been identified in MELAS patients.26–28

    Given the phenomenon of heteroplasmy, the number of pathological mutations, the variation in findings on muscle biopsy and an apparent ‘threshold effect’ (where there seems to be a minimum proportion of affected mitochondria needed in a given tissue to cause dysfunction), making a firm diagnosis of MELAS can be difficult. A negative genetic test or a normal muscle biopsy does not definitively rule out the condition.

    It has proven difficult to demonstrate the pathogenic link between the mutation and the presumed respiratory chain defect. In Pavlakis' original report, the authors studied in vitro enzyme activities from four of their patients but failed to demonstrate any specific and consistent defect. This is likely a reflection on the subtlety and complexity of mitochondrial DNA variation within and between individuals and the relative ‘grossness’ with which we can study oxidative enzyme function. Further small studies have attempted to link specific mutations with specific oxidative enzyme dysfunction.29 However, these are typically small with conflicting results and the link remains obscure.

    Treatments

    Much of research into MELAS, and the other mitochondrial cytopathies, in the first few decades of their recognition amounted to scientific stamp collecting with much emphasis on identifying and classifying different mutations and clinical phenotypes. There has been little progress in specific therapy despite many attempts at improving presumed oxidative enzyme deficiencies by administration of various coenzymes.30–32 None of these studies are large controlled trials and given that the results are modest at best, there is no substantial evidence for an effective treatment at present. A 2009 updated Cochrane review examined the evidence for treatments in all mitochondrial diseases and concluded that there was ‘no clear evidence supporting or refuting the use of any of these agents in mitochondrial disorders. No major side effects of these treatments were recorded.’33

    Coenzyme Q10

    Q10 has been used in many small-scale studies and case reports in an effort to compensate for the underlying oxidative enzyme dysfunction. In theory, Q10 could have a therapeutic effect by mediating electron transport among complexes I, II and III, thereby non-specifically providing additional components of the chain. Numerous authors have reported various successes with it in small-scale studies. Some include measurements of biochemical function in an effort to rationalise the therapeutic link. Bresolin and colleagues reported a two-step trial involving 44 patients with mitochondrial disease in 1990.34 The initial step was unblinded and suggested an improvement in postexercise lactate levels after administration of Q10 in some patients. The subsequent blinded component failed to demonstrate the same change. Given the lack of data but relative safety of Q10 some recommend a trial of treatment in all patients with mitochondrial disease. It has poor penetration of the central nervous system, which may, in part, explain the general lack of apparent efficacy.

    Idebenone

    This compound was originally developed with a view to treating dementia but has been reported in numerous cases of MELAS.35 It functions as a free-radical scavenger and bypasses complex I. There is an ongoing randomised, double-blind phase II clinical trial examining idebenone in MELAS.

    L-arginine

    L-arginine can act as a nitric oxide donor, thereby promoting vasodilatation and in theory ameliorating the acute cerebrovascular dysfunction in MELAS. Administration has been trialled in both acute stroke and long term in MELAS.32 36 37 These studies demonstrated that plasma concentrations of L-arginine were lower in MELAS patients during acute stroke-like episodes and that MELAS patients have endothelial dysfunction as assessed by flow-mediated vasodilation. L-arginine infusion during exacerbations improved symptoms. Two-year oral L-arginine was also suggested to normalise serum levels. However, these were again small studies that have yet to be replicated on a larger population.

    Dichloroacetate

    Dichloroacetate has also received some attention as a therapeutic agent in mitochondrial disease, and has much the same inconclusive case-report level evidence as Q10. In theory, it acts by inhibiting the phosphorylation of pyruvate dehydrogenase complex, which thereby remains an active oxidiser of pyruvate to acetyl coenzyme A. There is then less pyruvate substrate available to produce lactate. This has been considered a potential therapeutic strategy because conditions like MELAS are characterised by a raised plasma lactate due to the metabolic failure. However, whether this excess lactate is a prime player in the pathogenesis of the clinical features or a mere by-product of the underlying enzyme defects is debatable. The use of dichloroacetate has generally been in small studies or case reports.38 A 3 year randomised, double-blind, placebo-controlled crossover trial was reported in 2006.39 This study was stopped early due to the very high incidence or worsening of peripheral neuropathy in the treatment arm.

    Exercise training and ketogenic diets

    The phenomenon of heteroplasmy, and the observation that the proportion of normal and abnormal mitochondria within a tissue type can change over time, forms the hypothetical basis for both exercise training and ketogenic diets in mitochondrial diseases. Exercise training in patients with muscle-specific mitochondrial mutations has been shown to increase the proportion of mitochondria with normal wild type genomes and to improve the metabolic function of muscle.40 Similarly, a ketogenic diet has shown to increase mitochondrial biogenesis and result in an increased proportion of wild type mitochondrial DNA in humans and a delay in disease progression in an animal model of mitochondrial disease.41 42 These approaches have yet to be trialled in MELAS.

    Mitochondrial transplantation

    Patients with MELAS often fear passing on the condition to future generations. Unfortunately, due to the mitochondrial pattern of inheritance and the variation due to heteroplasmy and genetic bottlenecking,43 it is not possible to predict the risk of passing on the mutation or the likelihood of a clinical phenotype. An emerging strategy in mitochondrial disease, currently still at a basic science level, is to attempt a so-called mitochondrial transplant. Nuclear transfer techniques have now allowed the transfer of human pronuclei from a normal zygote to a recipient with a mitochondrial mutation that has had most of the mitochondria removed.44 This has been successfully developed to the blastocyst stage in vitro, the current legal limit within the UK. This approach could hypothetically allow an affected female patient to use her oocyte and partner's sperm to form a viable embryo, with the addition of a mitochondrial genome from a third party oocyte. This clearly brings the treatment of mitochondrial diseases right to the boundaries of contemporary biotechnology, healthcare and ethics.

    Summary

    The mitochondrial mutation m.3243A>G is probably the most prevalent of all mitochondrial mutations but the pathological and clinical spectrum it gives rise to is still being fully delineated. Many with the mutation never experience a significant clinical phenotype while others develop an early-onset mitochondrial cytopathy in childhood with short stature and rapid decline (the classic MELAS syndrome) and others still a later-onset form of MELAS with a less rapidly progressive course. In addition the clinical syndrome of MELAS can be caused by other mitochondrial mutations, further adding to the heterogeneity of this disorder.

    MRI usually demonstrates typical migrating cortical and subcortical grey matter lesions not confined to single arterial territories. MRS reveals elevated lactate in non-acute ischaemic regions.

    Muscle biopsy shows the classical ragged-red fibres of mitochondrial disease, along with other typical features, and can be used to detect the mitochondrial mutation. Urine testing is now emerging as the basis for less invasive preferred testing for the commoner mutations.

    Treatment options remain limited and experimental but as our knowledge of the mitochondrial disorders increases we wait expectantly for future rational therapies.

    Main messages

    • Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) is an important, albeit uncommon, cause of stroke-like episodes in young people.

    • Due to the phenomena of heteroplasmy, the threshold effect and a range of pathogenic mutations, the diagnosis of MELAS can prove difficult because there is often no clear family history and a wide range of clinical phenotypes.

    • CT may be normal in MELAS. MRI is the modality of choice and shows characteristic migrating lesions typically in the cortical ribbon and deep grey matter.

    • Establishing a recognised genetic mutation is the crucial point in investigating MELAS.

    • Urine testing has emerged as the most clinically useful method for analysis of mitochondrial DNA.

    • Muscle biopsy remains important in cases without a detectable recognised mutation.

    Current research questions

    • How do the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode mutations cause cellular dysfunction?

    • Are there any simple biochemical therapies that can correct or compensate for the metabolic derangement?

    • Will ‘mitochondrial transplantation’ prove to be an ethical, safe and effective approach?

    Key references

    ▶ Bianchi MC, Tosetti M, Battini R, et al. Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic significance. AJNR Am J Neuroradiol 2003;24:1958–66.

    ▶ Goto Y, Nonaka I, Horai S. A mutation in the tRNALeu (UUR) gene associated with the MELAS subgroup of mitochondrial encenphalomyopathies. Nature 1990;348:651–3.

    ▶ Pavlakis SG, Philips PC, DiMauro S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481–8.

    ▶ Sarnat HB, Marin-Garcia J. Pathology of mitochondrial encephalomyopathies. Can J Neurol Sci 2005;32:152–66.

    ▶ Sheerin F, Pretorius PM, Briley D, et al. Differential diagnosis of restricted diffusion confined to the cerebral cortex. Clin Radiol 2008;63:1245–53.

    Self assessment questions (true/false; answers after the references)

    1. The following clinical features help distinguish MELAS from other mitochondrial disorders:

    1. Myoclonic seizures

    2. Hemiparesis

    3. Hemianopia

    4. Migraine

    5. Lactic acidosis

    2. The mitochondrial mutation m.3243A>G is the most commonly identified in MELAS.

    3. MELAS typically shows the following on brain imaging:

    1. Bilateral basal ganglia calcification on CT

    2. Focal areas of arterial stenosis on CT angiography

    3. Migrating, high signal T2 lesions preferentially affecting the cortical and subcortical grey matter on MRI

    4. Areas of restricted diffusion on DWI MRI sequences

    4. Serum and CSF lactate is usually decreased in MELAS patients.

    5. MELAS shows the following features on muscle biopsy:

    1. Ragged-red fibres on Gomori stain

    2. Ragger-red fibres faintly counterstain with oxidative enzymes

    3. Variation in fibre diameter

    4. COX-negative fibres among normal fibres

    Appendix

    1. There are few features with definitively distinguish the various mitochondrial disorders, however.

    1. False. Myoclonic seizures are also a hallmark of MERRF

    2. True

    3. True

    4. True

    5. False. This is a general feature of mitochondrial disorders

    2. True

    3. There are no pathognomic features on brain imaging; however, the use of MRS and serial MRI can offer strong support to a suspected mitochondrial disorder.

    1. Unclear. This is a non-specific finding in older patients but in younger patients with simple causes excluded it is abnormal and should prompt the consideration of a metabolic disorder

    2. False. Typically there are no areas of focal stenosis or suggestion of vasculitis. There may be hyperaemia in areas of infarction

    3. True. The predilection for grey matter is thought to be caused by the relatively high metabolic demand of neurons compared with axons and myelin in white matter

    4. True

    4. False. Serum and CSF lactate is usually increased in MELAS. Any cause of infarction will cause a rise in CSF lactate; however, MRS may be able to show a focally high level in regions not overtly ischaemic on MRI

    5. Muscle biopsy plays a key role in the diagnosis of mitochondrial cytopathies when genetic screening has proven negative.

    1. True. These are a hallmark of mitochondrial disease. They are caused by the irregular subsarcolemmal zone staining brightly due to the accumulation of abnormal mitochondria

    2. False. In contrast with degenerating and regenerating fibres, the ragged-red fibres of mitochondrial disorders are metabolically active and strongly stain for oxidative enzymes

    3. True

    4. True

    References

    1. ↵
      1. Pavlakis SG,
      2. Philips PC,
      3. DiMauro S,
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    Footnotes

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Written patient consent was obtained for the case report.

    • Provenance and peer review Not commissioned; externally peer reviewed.