| | 155th ENMC workshop: Polymerase gamma and disorders of mitochondrial DNA synthesis, 21–23 September 2007, Naarden, The NetherlandsReceived 15 October 2007 1. Introduction  Twenty-three clinicians and basic scientists from 14 countries gathered in Naarden, The Netherlands for the first ENMC workshop specifically focussing on a recently identified group of diseases due to disorders of mitochondrial DNA (mtDNA) synthesis. Over the last few years it has become clear that mutations in POLG (also referred to as POLG1), the gene coding for the catalytic subunit of the mtDNA polymerase, polγ, are a major cause of human disease. The principal aim of the workshop was to share knowledge and establish new collaborations to improve our ability to diagnose and treat patients with POLG mutations. This led to consensus statements on which patients to investigate, how to investigate and how to manage patients with suspected POLG disease. 2. Background Polymerase gamma is believed to be the only DNA polymerase within animal cells [1]. The first mutations of POLG were published in 2001 in families transmitting the mitochondrial disorder autosomal progressive external ophthalmoplegia (adPEO) [2]. Over the last five years, mutations in POLG have been identified in a wide range of mitochondrial diseases, including the childhood encephalomyopathy with liver failure (Alpers–Huttenlocher syndrome) [3], and adult onset spinocerebellar ataxia [4] – and a number of other isolated clinical syndromes including fatigue, muscle weakness, and muscle pain [5]. In addition, some family members also have parkinsonism and premature ovarian failure due to the same molecular defect [6]. It is becoming clear that POLG is a major human disease gene, possibly accounting for up to 25% of all patients with mitochondrial diseases. Mitochondria contain their own DNA (mtDNA) which codes for 13 polypeptides and 24 RNA molecules that are essential for oxidative phosphorylation. MtDNA is replicated by polγ which is composed of a 140-kDa catalytic subunit (p140) and a 55-kDa accessory subunit (p55) [1]. The catalytic subunit possesses DNA polymerase, 3′–5′ exonuclease, and 5′dRP lyase activities, whereas the accessory subunit is a DNA binding factor that confers high processivity on the protein complex by increasing its affinity to DNA [1], [7]. Mutations in POLG cause mtDNA depletion, or multiple secondary mutations of mtDNA [8]. These secondary mtDNA abnormalities are thought to be responsible for the clinical features of the disorder. Over 100 different POLG mutations have been described in the literature over recent years. However, rather than giving us a clear understanding, the situation has become more complex. Some mutations can behave as both dominant and recessive alleles, some patients have three or four mutations within the same gene, and polymorphic genetic variants (found in up to 4% of the population), also seem to modulate the phenotype [5]. It is also not clear why the same mutations can cause severe depletion of mtDNA in Alpers–Huttenlocher syndrome, and also cause a late-onset mild PEO phenotype. These observations make genetic counselling extremely difficult, and our rudimentary understanding of the pathophysiology limits our ability to develop new treatments. 3. Overview of the workshop The workshop began with an overview of the major clinical phenotypes associated with mutations in POLG in adults and children, followed by a discussion of the basic science underpinning the replication of mtDNA. There was a detailed discussion of the cellular, animal and in silico models of mtDNA replication and how these have informed our understanding of disease. Unusual clinical presentations were presented and discussed throughout the meeting, and the final session focussed on the diagnosis and management of patients with suspected and confirmed POLG mutations. This report summarises the major conclusions reached following two days of open discussion between the participants. A number of fundamental questions were highlighted at the start of the meeting. These formed the focus of subsequent presentations and discussions. 3.1. What is the mechanism of mtDNA deletion formation? Single large-scale deletions and multiple deletions have been associated with human diseases for nearly twenty years, but the actual mechanism producing the deletion has not been established. A number of hypotheses have been proposed, including slippage during replication, strand invasion, homologous recombination and oxidative damage leading to aberrant mtDNA repair [9], [10], [11]. Defining the actual mechanism will have important implications for prevention and treatment. 3.2. What leads to the accumulation of deletions? Studies on human tissue consistently show that high levels of a single mutated species are present within individual cells, pointing towards a clonal expansion [12], [13]. However, in patients with POLG mutations, multiple de novo deletions could develop within the same cell leading to the biochemical defect [14]. 3.3. Why are some POLG mutations dominant and others recessive? Although there is an emerging trend, for dominant late-onset-disease to be associated with mutations affecting the polymerase domain of polγ, and for recessive mutations to be scattered throughout the gene, the molecular explanation for this pattern is not understood. Mutations affecting the linker region of the protein are usually recessive, and are thought to affect interaction between the catalytic and accessory subunits [15], but this has only been confirmed for the A467T mutation [16]. 3.4. Why do different POLG mutations cause different secondary mtDNA defects? Recessive mutations tend to cause mtDNA depletion and present in childhood, whilst dominant mutations tend to cause adult onset-disease with multiple secondary deletions of mtDNA. Depletion, multiple deletions and multiple different point mutations may be present to varying degrees in association with different POLG mutations [14], although there is conflicting data [17], and the situation has not been fully resolved [18]. What drives the production of one type of mutation versus another is not understood, but it may contribute to the clinical spectrum. 3.5. Why is the accumulation of deletions tissue specific? The major clinical features found in patients with POLG mutations affect post-mitotic tissues (non-dividing cells, such as neurons, cardiac and skeletal muscle), and tissues with a low mitotic index (slowly dividing cells, such as liver). This may be reflective of a common mechanism underpinning the propagation of these secondary mtDNA defects, but this has not been formally proven. 3.6. Will the spectrum of phenotypes associated with POLG mutations continue to expand? Although initially thought to cause a number of discrete phenotypes, published cases and new cases presented at the workshop demonstrate the overlapping spectrum of disease from early neonatal life to senescence [5]. These will be discussed in a separate section of the report. 3.7. What is the role of polγ in human ageing? The phenotype in two mouse models with POLG mis-sense mutations mimic some of the features of human ageing [19], [20], and multiple deletions of mtDNA have been detected in post-mitotic human tissues taken from healthy aged individuals, albeit at low levels [13], [21]. This raises the possibility that disruption of polγ contributes to the ageing process. On the other hand, patients with POLG mutations do not appear to age prematurely. Further work is required to address this potentially important issue. 3.8. What is the relative importance of other genes in disorders of mtDNA maintenance? The two other major genes involved in mtDNA maintenance are PEO1 (previously known as C10Orf2) encoding the mitochondrial helicase Twinkle [22]; and SLC25A4, encoding adenine nucleotide translocator 1, Ant 1 [23], which cause autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple deletions of mtDNA (Table 1). The only other gene known to cause dominant PEO is POLG2 which codes for the accessory β-subunit of polγ, p55 [24]. Recessive mutations in POLG can also cause PEO [2] and ataxia, with neuropathy and epilepsy [25]. Recently, recessive mutations in PEO1 have been described in children presenting with an Alpers-like phenotype [26], [27]. Genes causing autosomal recessive mtDNA depletion syndromes include TP encoding thymidine phosphorylase [28]; TK2, encoding thymine kinase [29]; DGUOK, encoding deoxyguanosine kinase [30], SUCLA2 [31]; MPV17 [32]; RRM2B [33]; and SUCG1 [34]. Mutations in these genes are rare, and the underlying gene defect has yet to be characterised in many adults with multiple mtDNA deletions and children with mtDNA depletion.  | Alper–Huttenlocher-like syndromes (mutations in POLG, PEO1 and MPV) | | | Autosomal progressive external ophthalmoplegia (mutations in POLG, POLG2, PEO1 and SLC25A4) | | | Encephalomyopathy and liver failure (mutations in DGUOK) | | | Fatal infantile lactic acidosis (mutation in SUCG1) | | | Hypotonia, encephalopathy, renal tubulopathy, lactic acidosis (mutation in RRM2B) | | | Hypotonia, movement disorder and/or Leigh syndrome with methylmalonic aciduria (mutations in SUCLA2) | | | Infantile myopathy/spinal muscular atrophy (mutations in TK2) | | | Mitochondrial neurogastrointestinal encephalomyopathy (thymidine phosphorylase deficiency – mutations in TP) | | | | |
At least four cases of possible digenic inheritance have been described, where potentially pathogenic mutations have been identified in two different genes involved in mtDNA maintenance in the same patient with multiple mtDNA deletions (including those described in [5], [35]). This could be due to the combined effect of both substitutions compromising the function of the mtDNA replisome – but this has not been firmly established, and further work is required to confirm or refute this possibility. 4. The prevalence of POLG mutations The prevalence of disease due to POLG mutations is not known, but the combined experience of the participants is testimony to the large increase in the number of patients being diagnosed throughout Europe. The recommendations made in this report are based on over 270 patients with established pathogenic POLG mutations that have been studied by the participants, and a further 83 sporadic cases who have only one mutated allele. 5. The expanding and overlapping phenotypic spectrum of disease 5.1. Classical presentations The first pathogenic mutations in POLG were identified in families with autosomal dominant chronic progressive external ophthalmoplegia (adPEO, MIM 157640) [2]. A high incidence of psychiatric disease, a parkinsonian syndrome and primary gonadal failure have also been documented in some families transmitting dominant POLG mutations [6], [36]. Compound heterozygous POLG mutations were also identified in patients with sporadic and recessive PEO [2]. Many recessive cases have cerebellar ataxia and a profound peripheral neuropathy, which is axonal in the vast majority of cases. This is similar to the previously described SANDO syndrome (sensory ataxic neuropathy with dysarthria and ophthalmoparesis) [4]. Recessive POLG mutations also present with adult onset ataxia without ophthalmoplegia (also called mitochondrial recessive ataxia syndrome, MIRAS) [37], [38], which is more common in Scandinavia than Friedreich’s ataxia [38]. Recessive POLG mutations are also the major cause of the Alpers–Huttenlocher syndrome, which is a severe hepatoencephalopathy with intractable seizures and visual failure which presents in early childhood and is associated with depletion of mtDNA in affected tissues [3], [39], [40], [41], [42], [43], [44]. 5.2. Novel phenotypic aspects Following the diagnosis of a large number of cases of recessive POLG mutations in Scandinavia, there have been a number of recent studies describing the phenotype in detail. Ophthalmoparesis is a late feature in these patients. Epilepsy or complicated migraine with occipital aura are very common features, often pre-dating the development of ataxia by many years [38], [45]. The epilepsy is often focal, typically affecting the right limb and presenting as epilepsia partialis continua. Status epilepticus has a very poor prognosis, being the terminal event in many patients. Characteristic neuro-imaging findings are currently being defined. Unusual phenotypes presented at the workshop included neonatal hypotonia mimicking spinal muscular atrophy, and a demyelinating polyneuropathy (now described in a number of cases, although it is not clear whether some of these early onset neuropathies could actually be due to hypomyelination). 5.3. Alpers syndrome and the Alpers–Huttenlocher syndrome Alpers syndrome is a childhood encephalopathy characterised by developmental delay and intractable epilepsy due to a number of different causes, including mutations in POLG. By contrast, the Alpers–Huttenlocher syndrome is characterised by liver failure in addition to the cerebral features of Alpers syndrome [44]. The vast majority, if not all cases of the Alpers–Huttenlocher syndrome are due to mutations in POLG. In ∼50% of cases, sodium valproate had been used before the onset of the liver failure, indicating the importance of avoiding this drug in children with unexplained encephalopathy. 5.4. Defining the disorder: clinical syndromes vs. a continuous spectrum of POLG disease A number of different defined clinical syndromes have been described in patients with POLG mutations (Table 2). However, the combined clinical experience of the participants was consistent with a continuous spectrum of disease from early childhood to late adult life, and it may not be possible to strictly categorise individual patients into discrete syndrome groups (Fig. 1). For example, adults with MIRAS also appear to be sensitive to sodium valproate, and develop an acute encephalopathy with intractable epilepsy – this is reminiscent of the Alpers–Huttenlocher syndrome, which is classically a disease of early childhood. The participants therefore recognised the importance of defining a simple unifying diagnosis of “POLG disease”, characterised by PEO, or cerebellar and sensory ataxia, complicated occipital migraine with intractable epilepsy, or encephalopathy with liver failure in childhood. On the other hand, there was general agreement that some of the more common syndrome names should be used (such as the Alpers–Huttenlocher syndrome) because clinicians recognised these diagnoses, and because the clinical and histopathological features of this syndrome in particular are well described in standard textbooks. | Alpers–Huttenlocher syndrome (AHS) | | | Chronic progressive external ophthalmoplegia (CPEO) | | | Infantile hypotonia/spinal muscular atrophy (SMA) | | | Mitochondrial encephalomyopathy with ragged-red fibres (MERRF) | | | Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) | | | Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) | | | Mitochondrial recessive ataxia syndrome (MIRAS) | | | Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) | | | | |
6. Consensus view on best practice for the investigation of patients with suspected POLG disease 6.1. Who should be investigated? The expanding spectrum of phenotypes found in patients with POLG mutations presents a major challenge to clinicians. However, there was a consensus view that POLG should always be considered in the following patients: 1.PEO with a positive family history and/or multiple mtDNA deletions in a skeletal muscle biopsy. 2.Ataxia with an axonal sensorimotor neuropathy, especially if there is epilepsy. 3.All children with an unexplained encephalopathy, especially if there is evidence of liver dysfunction. POLG should be considered in any child or adult presenting with an unexplained constellation of neurological features, particularly if there is evidence of liver involvement, which is otherwise unusual in adults with mitochondrial disease. A previously published algorithm drew a distinction between children (<16 years of age) and adults (>16 years of age) [5]. This distinction is, however, artificial and largely reflects the referral patterns to child and adult physicians. Given the overlapping phenotypic spectrum, a general scheme of investigation was proposed, irrespective of age (Fig. 2). 6.2. Approach to investigation – the role of specialist centres Although the approach to investigating suspected POLG disease appears to be superficially straight forward, this is not the case. Technical difficulties in quantifying the amount of mtDNA and multiple mtDNA deletions, the lack of published data on the normal range for the mtDNA content in various tissues at different stages of development, and the presence of multiple mtDNA deletions in the skeletal muscle of healthy older individuals, present major challenges when investigating suspected disorders of mtDNA maintenance. In addition, the presence of multiple base substitutions in the same patient (even those with common pathogenic alleles such as A467T), isolated heterozygous substitutions in sporadic cases that are presumed to be recessive, and the apparent high frequency of common SNPs in patients with POLG disease, make it difficult to interpret the molecular data and give appropriate advice for genetic counselling. It is therefore strongly recommend that clinicians who suspect POLG disease should contact a specialised laboratory before commencing investigation, to ensure that the results are interpreted correctly – whether positive or negative. 6.3. Investigation algorithm – a guide Differences in the referral patterns between centres, and particularly the ease of obtaining frozen muscle for the analysis of secondary mtDNA abnormalities, explain minor differences in the approach to investigation. However, there was general agreement with the approach presented in Fig. 2. In patients with a well-defined clinical syndrome due to POLG mutations, it is appropriate to proceed directly to POLG gene analysis on a blood or buccal DNA sample. Some laboratories immediately check for the two common pathogenic alleles A467T and W748S, which may give the diagnosis or give a clue to the diagnosis if only one heterozygous substitution is detected. This is done for speed in the acute situation, as may be the case for a child presenting with an acute encephalopathy. Other laboratories sequence the POLG gene as a first step, because of the possibility of identifying other substitutions which were present in up to 1/3 in one series [5]. The second group of patients are those who do not have a well recognised POLG-related syndrome, but have suspected mitochondrial disease or features that form part of the classical POLG syndromes (oligosymptomatic POLG disease, Fig. 2). For these patients, a systematic approach is preferable, which begins with a tissue biopsy from a clinically affected organ which must be frozen and not fixed (usually skeletal muscle or liver, but not skin fibroblasts which give inconsistent findings). The aim is to look for biochemical evidence of mitochondrial dysfunction. In adults, histochemistry of skeletal muscle usually gives the answer, although this may not always be abnormal, particularly if the biopsy is taken at an early stage in the disease. In children, biochemical studies of the individual respiratory chain complexes is usually abnormal. mtDNA studies are usually performed in parallel to these biochemical studies, again on DNA extracted from frozen tissue from an affected organ. The presence of mtDNA depletion or multiple mtDNA deletions should lead to POLG sequencing. It should be remembered that neither the biochemical nor the mtDNA based tests are comprehensive, as patients with POLG mutations have been described without biochemical or mtDNA abnormalities in liver or muscle, presumably because these tissues are only mildly affected. However, if there is liver failure, severe depletion of mtDNA in liver would be expected in cases with POLG mutations. These complexities illustrate the difficulties faced when investigating these patients, which illustrates the importance of carrying out these investigations in a specialised laboratory. Ultimately the decision to sequence POLG is clinical, and based on clinical suspicion in the light of supporting clinical and laboratory investigations. 6.4. Evaluating which mutations are pathogenic and which are polymorphic Although many patients are found to have one or more well-established pathogenic alleles, a large proportion have novel base substitutions. Confirming that these are pathogenic can be difficult. The standard approach is no different to other nuclear disease genes, and involves: (1) showing the putative pathogenic allele segregates with the phenotype within the family; (2) showing the mutation is absent from controls; (3) showing that the substitution alters a functionally important amino acid residue. This is usually based on: (a) conservation of that residue across diverse species, and (b) biochemical evidence that the allele alters function of polγ. However, this simple approach presents challenges. First, although a well-established biochemical assay has proven invaluable [46], [47], a readily available and quick functional assay of polγ is not available. Such an assay would prove invaluable in the future. Second, well recognised SNPs also alter highly conserved residues (such as E1143G [15]). Although the role of the E1143G substitution is still under debate, this illustrates that disruption of a conserved residue is not a guarantee of pathogenicity. Third, it is critically important to screen a large number of population matched controls. For example, the Y831C substitution was found in two siblings with ophthalmoplegia and parkinsonism, but not in controls [48], pointing towards a pathogenic role. However, two groups subsequently identified the same substitution in age-matched controls [49], [50] questioning its pathogenic role. Finally, in practice it is rarely possible to demonstrate convincing segregation within the family because pedigrees are often small. For example, the G517V substitution which was shown to segregate in one three generation family [5] has subsequently been found in control subjects in different European countries, also questioning its pathogenic role. Further confirmation with segregation in a separate family with a clear-cut disorder of mtDNA maintenance provides supportive evidence of pathogenicity, but this is rarely possible. Until a functional test becomes widely available, then it is only possible to conclude that a mutation is definitely pathogenic only when it has been described before in two or more families with the same phenotype with a clear-cut secondary defect of mtDNA. De novo mutations in single families can only be considered to be “probably pathogenic” when they fulfil the above criteria, and specifically, for recessive mutations the allele must be uncommon in the population (<5% frequency), and for dominant mutations, the mutation must not be detected in at least 200 population-matched control individuals. 6.5. The role of polymorphisms in modifying the disease phenotype A number of small studies have reported a high frequency of ostensibly neutral SNPs in patients with multiple deletions of mtDNA or sporadic cases with only one mutated allele (For example, [51], [52]). The E1143G substitution is the best example. Although present in ∼4% of control subjects, paradoxically it alters a highly conserved residue in the polymerase domain of polγ and alters function of the enzyme in vitro [15]. Further work is required in this area. 7. Consensus view on best practice for the management of patients with POLG disease 7.1. Genetic counselling Although POLG mutations obey the same basic rules of autosomal inheritance, the situation is complicated by the presence of more than one potential mutated allele on each chromosome, the role of SNPs that modify the phenotype, and the description of late-onset mild phenotypes in carriers of recessive alleles, including A467T which is present in up to 0.7% of the population [45], [53], [54]. In addition, the clinical penetrance of most pathogenic POLG alleles has yet to be established. Counselling is therefore not straightforward, and this should only be done after careful consultation with physicians who specialise in mitochondrial diseases. 7.2. The use of sodium valproate There are a large number (>40 cases) where liver failure followed the use of sodium valproate in patients with POLG disease. In most cases, this has led to the terminal illness. Sodium valproate should therefore be avoided in all patients with proven or suspected POLG disease. Liver failure has also been described in adults with recessive POLG mutations, so this recommendation applies throughout life. Sodium valproate toxicity may be less common in adults, particularly those with dominant mutations where there are well documented cases of long-term sodium valproate use without complications. However, given the potential severity and the large number of alternative anticonvulsants in current use, this drug is best avoided in this group of patients. 7.3. The treatment of seizures Seizures are common in adults and children with recessive POLG mutations. These should be treated aggressively (without using sodium valproate) because intractable epilepsy and status epilepticus have a very poor prognosis in patients with POLG disease. Patients who have had a prolonged period of continuous seizure activity rarely regain full neurological function, and status epilepticus was the terminal event in many patients, being refractory to all therapies including barbiturate-induced coma or a period of anaesthesia. Different anticonvulsants have been tried, with varying success. It is currently not possible to say which agents should be first or second line, or what the best approach is for the management of status epilepticus. 8. Future direction It is clear that POLG mutations are a major cause of neurological disease, and the phenotypic spectrum continues to expand. Distinct phenotypes are emerging that are instantly recognisable as “POLG disease”, and the range of different mutations and SNPs is growing exponentially. Already it is clear that some specific widely available treatments should be avoided in suspected and confirmed cases, and we are starting to understand the natural history of the different disease phenotypes. There is clear need to assimilate clinical and molecular data to resolve some of the complex questions facing clinicians and laboratory scientists working in this area, and the involvement of a specialist with up-to-date knowledge of this rapidly evolving field is strongly recommended. At this workshop, the major centres in Europe agreed to pool their resources in the following way: (i) to ensure that the established database of POLG mutations (http://tools.niehs.nih.gov/polg/) is kept up to date, by communicating any results “in press” to the curator of the site; (ii) to compile a database of patients with sporadic disease who have single heterozygous substitutions that are thought to be pathogenic, but which cannot be confirmed to be pathogenic; and (iii) to compile a database of normal POLG sequences to act as a reference for novel changes. The number of POLG sequences from healthy controls available is in excess of 1100, and in controls with other neurological diseases is greater than 350, forming a substantial resource which will be made public through a web interface. 9. Participants | Laurence Bindoff | Bergen, Norway | | | Annette Boersen | ENMC | | | Patrick F. Chinnery | Newcastle, UK | | | William Copeland | North Carolina, USA | | | Rene De Coo | Rotterdam, The Netherlands | | | Maaike De Vries | Nijmegen, The Netherlands | | | Iliana Ferrero | Parma, Italy | | | Christopher Freyer | Stockholm, Sweden | | | Bert van den Heuvel | Nijmegen, The Netherlands | | | Ian J. Holt | Cambridge, UK | | | Rita Horvath | Munich, Germany | | | Anne Lombès | Paris, France | | | Ramon Marti | Bareclona, Spain | | | Anders Oldfors | Gothenburg, Sweden | | | David C. Samuels | Virginia, USA | | | Bert Smeets | Maastricht, The Netherlands | | | Jan Smeitink | Nijmegen, The Netherlands | | | Hans Spelbrink | Tampere, Finland | | | Joanna D. Stewart | Newcastle, UK | | | Anu Suomalainen | Helsinki, Finland | | | Mar Tulinius | Gothenburg. Sweden | | | Gert Van Goethem | Antwerp, Belgium | | | Jiri Zeman | Prague, Czech Republic | | | Massimo Zeviani | Milan, Italy | | | | |
Acknowledgements This workshop was made possible by the financial support of the European Neuromuscular Centre (ENMC) and its main sponsors and associated members: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Österreichische Muskelforschung (Austria), Vereniging Spierziekten Nederland (The Netherlands), and ENMC associate member: Asociacion Española contra las Enfermedades Neuromusculares (Spain). References [1]. [1]Kaguni LS. DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem. 2004;73:293–320. MEDLINE |
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a Mitochondrial Research Group and Institutes of Neuroscience and Human Genetics, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK b Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children’s Mitochondrial Disorders, Foundation “C. Besta” Neurological Institute – IRCCS, Milan, Italy  Corresponding author. Tel.: +44 191 222 8334; fax: +44 191 222 8553.
PII: S0960-8966(07)00762-6 doi:10.1016/j.nmd.2007.11.005 © 2007 Elsevier B.V. All rights reserved. | |
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