Brain Advance Access published online on April 17, 2007
Brain, doi:10.1093/brain/awm067
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Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression?
1Inserm, U582, Paris F-75013, France, 2Université Pierre et Marie Curie-Paris6, IFR14, Paris F-75013, France, 3AP-HP, hôpital Robert Debré, Centre de référence des Maladies Héréditaires du Métabolisme, Paris F-75020, France, 4Institut de Myologie, hôpital Pitié-Salpêtrière Paris, F-75013, France and 5AP-HP, hôpital Pitié-Salpêtrière, Biochimie, Paris F-75013, France
Correspondence to:
Dr Anne Lombès, Inserm U582, Institut de Myologie, Groupe hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris Cedex, France E-mail: a.lombes{at}myologie.chups.jussieu.fr
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Summary |
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The prognosis of chronic progressive ophthalmoplegia with large-scale mitochondrial DNA (mtDNA) may strikingly vary from mild slowly progressive myopathy to severe multi-organ involvement. Evaluation of the disease course at the beginning of the disease is reputed impossible. To address the existence of predictive prognostic clues of these diseases, we classified 69 patients with chronic progressive ophthalmoplegia and large size mtDNA deletion into two groups according to the presence of manifestations from brain, inner ear or retina. These manifestations were present in 29 patients (CPEO/+N group) and absent in 40 patients (CPEO/–N group). We retrospectively established the clinical history of the patients and characterized their genetic alteration (amount of residual normal mtDNA molecules, site, size and percentage of the mtDNA deletion in 116 DNA samples from muscle, blood, urinary and buccal cells).
In both clinical groups, the disease was progressive and heart conduction defects were frequent. We show that the CPEO/+N phenotype segregated with severe prognosis in term of rate of progression, multi-organs involvement and rate of survival. Age at onset appeared a predictive factor. The risk to develop a CPEO/+N phenotype was high when onset was before 9 years of age and low when onset was after 20 years of age. The presence and proportion of the mtDNA deletion in blood was also significantly associated with the CPEO/+N phenotype.
This study is the first to establish the natural history of chronic ophthalmoplegia with mtDNA deletion in a large series of patients and to look for parameters potentially predictive of the patients’ clinical course.
Key Words: mitochondrial disease; deletion; Kearns–Sayre syndrome; CPEO; natural history
Abbreviations: CPEO, chronic progressive ophthalmoplegia; mtDNA, mitochondrial DNA
Received October 23, 2006. Revised February 14, 2007. Accepted March 12, 2007.
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Introduction |
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Mitochondrial diseases have strikingly diverse clinical presentations, which renders it difficult to distinguish definite phenotypes. Accordingly, their clinical classification has always been the matter of much debate (Berenberg et al, 1977
; Bastiaensen et al, 1978). Indeed, genotype/phenotype relationship is often very complex in mitochondrial diseases, especially diseases due to mitochondrial DNA (mtDNA) alterations. Single large-scale mitochondrial DNA (mtDNA) deletions are a good example of that situation. They were the first identified genetic cause of mitochondrial disease (Holt et al, 1988) and have a prevalence between 1.2/100 000 (Chinnery et al, 2000) and 2.9/100 000 (Remes et al, 2005) in adults. They have been found responsible for diverse clinical phenotypes encompassing, at one extreme, very severe infantile cases with Pearson syndrome (Pearson et al, 1979; Lacbawan et al, 2000) and, at the other extreme, diseases with a later onset and chronic progressive ophthalmoplegia (CPEO) as part of otherwise quite diverse clinical presentations. Kearns–Sayre syndrome (KSS) (MIM 530000
[OMIM]
) is defined by CPEO beginning before 20 years of age and associated to retinal pigmentary degeneration and at least one of the following signs: heart block, cerebellar ataxia or elevated cerebrospinal fluid protein concentration (Kearns and Sayre, 1958; Shy et al., 1967; Berenberg et al, 1977). Although no large survey of the natural history of KSS has been performed to-date, progressive involvement of new organs, severe handicap and reduced life expectancy appear common. In contrast to KSS, some patients with CPEO and mtDNA deletion present with a relatively mild disease involving only muscle (Holt et al, 1988; Moraes et al, 1989). The disease of these patients is often named isolated CPEO but it has no MIM number owing to the uncertainty about its existence as an autonomous clinical entity. Indeed, numerous patients present with ‘border disease’, often termed as ‘severe CPEO’, ‘CPEO+’ or ‘incomplete KSS’ as they do not fulfil the criteria for KSS but are associated with manifestations from tissues other than muscle (Drachman, 1968; Berenberg et al., 1977; Moraes et al, 1989). It has been proposed that all the clinical presentations associated with single large size mtDNA deletions belong to a unique entity. This notion is supported by the frequent ‘border cases’ (Zeviani et al, 1988; Holt et al, 1989; Moraes et al, 1989) and by the presence of identical mtDNA deletions in patients with different clinical presentation (Holt et al, 1989; Moraes et al, 1989). Furthermore, some patients with Pearson syndrome who have survived early infancy have secondarily developed KSS (Mcshane et al, 1991; Rotig et al, 1995) and exceptionally mothers with isolated CPEO have given birth to a child with Pearson syndrome (Poulton et al, 1991; Bernes et al, 1993; Shanske et al, 2002).
The prognosis of the different forms of CPEO may however differ dramatically and its prediction obviously represents a major issue for the patients. Numerous studies have therefore searched for a link between disease severity and morphological, biochemical or molecular parameters. These studies were faced with the constant heteroplasmy of the mutant mtDNA, i.e. the coexistence of wild-type and deleted mtDNA molecules within each cell, which may strikingly differ between cells of the same organ (Sciacco et al, 1994) and between organs of the same patient (Hurko et al, 1990; Shanske et al, 1990; Brockington et al, 1995). Clinical severity of the disease did not correlate with the site or proportion of the deletion (Zeviani et al, 1988; Holt et al, 1989; Moraes et al, 1989; Yamamoto et al, 1991). The tissue distribution of the deletion was proposed to be an essential prognostic parameter. However, tissue distribution could not be the sole parameter as, when all parameters were analysed in a single organ as muscle, the respiratory chain activities appeared independent from the site, size or percentage of the mtDNA deletion (Holt et al, 1989; Moraes et al, 1989; Gerbitz et al, 1990). The relevance to phenotype of associated mtDNA rearrangements, such as duplications, could not be unambiguously demonstrated (Poulton et al, 1994; Brockington et al, 1995; Manfredi et al, 1997; Odoardi et al, 2003). The residual amount of normal mtDNA, which has been more rarely measured than the proportion of the mtDNA deletion, may have represented the critical parameter for respiratory capacity. It appeared related to respiratory defect at the level of single-muscle segment (Hammans et al, 1992; Oldfors et al, 1992; Auré et al, 2006), but this was not the case at the level of whole muscle fragment (Auré et al, 2006).
There is at present no predictive criteria for the clinical progression of CPEO associated with mtDNA deletions. To address the possibility of evaluating prognosis at the beginning of the disease, we retrospectively established the natural history of the disease of 69 patients who were followed over a long period of time. We showed that the presence of sensorial or cerebral symptoms segregated with severe prognosis in term of rate of progression, tissular extension and rate of survival. We looked for prognostic indicators in the patients’ initial clinical presentation and molecular characteristics (site, size or proportion of mtDNA deletion, amount of residual normal mtDNA and tissue distribution of the deletion). We found that the age at onset and the amount of mtDNA deletion in blood were predictive parameters.
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Patients
Patients with single mtDNA deletion in skeletal muscle were identified by Southern blot analysis of the patients’ muscle total DNA. The complete clinical charts of 69 patients were available. Most patients were followed either in the Institute of Myology, Paris or in the Metabolic Diseases centre of Robert Debré Hospital, Paris.
For each patient, the natural history of the disease was retrospectively established with special emphasis on the age at onset of each symptom: ptosis, ophthalmoplegia, diplopia, intolerance to exercise (easy fatigue, pains, cramps during exercise), muscle weakness (topography, need for a wheelchair), dysphagia, dysphonia, cerebellar ataxia, pyramidal symptoms, movement disorders, brain imaging alterations, peripheral neuropathy (clinical symptoms and/or on electromyography), heart conduction defect (electrocardiogram) and pacemaker implantation, cardiomyopathy (echocardiography), diabetes, other hormonal manifestations (defect of growth hormone, of parathyroid hormone), deafness (symptomatic and sometimes confirmed on audiogram), retinal degeneration (on fundoscopy or on electroretinogram), pancreatic insufficiency and haematological alterations (anaemia, lymphopenia, neutropenia). Failure to thrive for children as well as weight and height for adults were recorded.
Considering that the cerebral symptoms were most significant for the clinical outcome, we classified patients into two groups: patients who presented with brain symptoms such as cerebellar ataxia, movement disorder, pyramidal syndrome or dementia were included in a group named CPEO/+N for CPEO with neurological manifestations. Although not a sign of central nervous system involvement, the presence of deafness and/or retinitis pigmentosa was also considered sufficient to include patients into the CPEO/+N group. Patients with inner ear or retina alterations were indeed considered at high risk to later develop a brain disease because of the close embryological relationship of brain, inner ear and retina. In contrast, despite its previous association with KSS, heart conduction defect was not considered sufficient to include a patient in the CPEO/+N group as heart conduction tissue derives from mesoderm, an embryologic origin different from that of brain (Cheng et al, 1999). With these inclusion criteria, the CPEO/+N group included 29 patients. The patients without any symptom from brain, inner ear or retina were included in a second group named CPEO/–N for CPEO without neurological symptoms. It included 40 patients.
Methods
DNA extraction
DNA extraction from whole muscle was performed using standard methods based upon treatment by proteinase K and SDS, phenol/chloroform extraction and isopropanol precipitation. DNA extraction from leucocytes, urine cells and buccal cells was performed using QIAamp DNA Mini Kit extraction (Qiagen) following manufacturer's instructions.
Identification of deletion breakpoints and search for the presence of mtDNA deletion in non-muscle fragments
Search for deletions was performed by PCR amplification of the mtDNA region encompassing the deletion breakpoints. For identification of the deletion breakpoints, it followed by its direct sequencing in both directions on an automated sequencer (Applied Biosystems) with the Dynamic terminator Cycle Sequencing Kit (Amersham Biosciences).
Quantification of normal and total mtDNA species
Quantification was performed by real-time PCR using LightCycler FastStart Reaction SYBR Green I kit (Roche), following manufacturer's instructions, with assay conditions (magnesium concentration, annealing temperature and primers concentration) set up such as the amplification had an efficiency above 95% and was specific, giving one single peak on the fusion curve of amplified fragments.
Total mtDNA was quantified by amplification of a fragment of the 12S mtDNA gene (from nucleotide 1195 to 1305), which was always spared by the mtDNA deletion. Standards were provided by serial dilutions of linearized plasmid vector pGEM-T Easy (Promega) containing the entire 12S mtDNA gene (from nucleotide 109 to 1714) as an insert. Normal mtDNA was quantified by amplification of the mtDNA fragment from nucleotide 11614 to 11778, which was included in the deleted mtDNA region of all the patients. Standards were provided by linearized plasmid vector pGEM-T Easy (Promega) containing the mtDNA fragment from nucleotide 10739 to 11839 as an insert.
The proportion of the deletion was then calculated from the amount of normal and of total mtDNA. Nuclear DNA was quantified by amplification of the region from nucleotide 4401 to 4601 of the 28S gene. Standards were provided by serial dilutions of total DNA from normal fibroblasts.
As quantification of the different mtDNA species was based upon PCR amplification, it could be applied to very little amount of DNA and therefore to DNA extracted from cells of the urinary sediment or from buccal mucosa in addition to blood or muscle. The presence and proportion of mtDNA deletion was analysed in 116 DNA samples from muscle, blood, urinary or buccal cells. Each quantification was performed in duplicates. Results were expressed as mean and Standard Error to the Mean (SEM) of mtDNA copies per 10 pg of genomic DNA, which roughly corresponds to the amount of DNA in a normal diploid genome. All standard plasmids were purified with Nucleobond AX (Macherey-Nagel), linearized and quantified by fluorometry using SybrGreen I and 
phage DNA cut with HindIII as standard.
Statistical analyses
Comparison of quantitative parameters between groups was performed by the non-parametric Mann–Whitney test. Correlation analyses were done with the non-parametric Spearman correlation test. Comparison of proportions was performed with the chi square test. Comparison of survival rate was performed with the log-rank test. A P-value below 0.05 was considered significant.
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Results |
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Prognosis was more severe in the CPEO/+N group
The median duration of follow-up was similar in the two groups of patients (P = 0.85). It was 22.0 years in the CPEO/+N group versus 21.0 years in the CPEO/–N group (5% confidence interval 6.7–51.2 and 4.0–44.0 for CPEO/+N and CPEO/–N group, respectively). The CPEO/+N group included 16 patients who fulfilled the diagnostic criteria of KSS and 13 additional patients with cerebral symptoms and/or deafness or retinal degeneration. The presentation of these patients is summarized in Tables 1 and 2. Median duration of the follow up was similar in the patients with or without KSS (24.0 versus 21.5 years, respectively). Among the 40 patients of the CPEO/–N group, 8 had only ophthalmoplegia, 19 had limb muscle weakness in addition to ophthalmoplegia and 13 had a heart conduction defect in addition to ophthalmoplegia (three patients) or to ophthalmoplegia and limb muscle weakness (10 patients). The clinical phenotype of the patients of the CPEO group is summarized in Table 3. The retrospectively established natural history of the two clinical groups is schematized in Fig. 1 for the manifestations common to both groups and in Fig. 2 for the manifestations specific for the CPEO/+N group. The progressive nature of the disease is clearly demonstrated in both CPEO/–N and CPEO/+N groups (Figs 1 and 3). Interestingly, in individual patients from both groups, the rate of progression appeared homogeneous for the different organs as shown by the tight correlation of the delays of onset of the signs from each organ. For instance, the delay of onset of limb muscle weakness correlated with that of heart conduction defect (P = 0.001; r = 0.601; 26 patients), dysphagia and/or dysphonia (P = 0.03; r = 0.421; 25 patients) or neurological symptoms (P < 0.0001; r = 0.861; 13 patients). Correlation with deafness showed the same trend without reaching significance but the number of patients was small (P = 0.12; r = 0.536; nine patients). These results indicate a parallel progression of non-embryologically linked organs in both clinical groups (heart conduction tissue and skeletal muscle in the CPEO/–N group, almost all organs in the CPEO/+N group). It is interesting to note that, outside heart conduction defect, all extra-muscle manifestations were observed in the CPEO/+N group despite the fact that their inclusion in the CPEO/+N group was only based on the presence of sensorineural manifestations (Fig. 3). These additional signs comprised endocrinological defects (diabetes, hypoparathyroidism, growth hormone defect), haematological anomalies (anaemia, lymphopenia, neutropenia) and renal tubulopathy.
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Clinical course was more severe in the CPEO/+N group than in the CPEO/–N group. Signs had a broader organ distribution in the CPEO/+N patients but they also evolved more rapidly. For instance, pacemaker had to be implanted in 65% of the CPEO/+N patients with heart conduction defect (11/17) compared to only 15% of the CPEO/–N patients (2/13) (P = 0.002). Five patients with CPEO/+N developed a cardiomyopathy with reduced ventricular contractility compared to none with CPEO/–N (P = 0.01). Globally, the CPEO/+N patients had reduced life expectancy. Five patients (four with KSS) out of the 29 CPEO/+N patients but none out of the 40 CPEO/–N patients died before the age of 45 years (P = 0.009). The cause of death was heart failure (two patients), respiratory failure (two patients) or multi-tissular failure (one patient).
Age at onset appears an important prognostic parameter
We searched for differences between the two groups of patients at the beginning of their disease, which would allow prediction of their progression. The onset of the disease occurred earlier in CPEO/+N than in CPEO/–N patients (Fig. 1). The median age at onset was 12.0 years (5% CI: 3.8–20.5 years old) for the CPEO/+N, whereas it was 17.5 years (5% CI: 9–39.5 years old) for the CPEO/–N patients (P < 0.001). Furthermore, in the CPEO/+N group, age at onset negatively correlated with the delay of onset of neurological symptoms (P = 0.01; r = –0.62; 15 patients) or of cardiac manifestations (P = 0.006; r = –0.63; 17 patients). Ophthalmoplegia (ptosis, diplopia or ophthalmoplegia itself) was the initial symptom for all the patients of the CPEO/–N group and for 24/29 (83%) patients of the CPEO/+N group. A presenting symptom different from ophthalmoplegia could therefore represent a prognostic parameter but that occurrence was observed in only five patients. No other initial clinical sign could differentiate the two clinical groups at onset of the disease. In particular, each symptom common to both group had similar frequency in each group (Fig. 3).
Among the diverse molecular parameters, only the presence and proportion of the mtDNA deletion in blood differed in the two clinical groups of patients
Identification of the deletion breakpoints was obtained in 64 patients (93%). As previously reported, the deletion size varied greatly (Fig. 4A). Its distribution was similar in the two clinical groups (Fig. 4A). The median deletion size was 4977 bp in the CPEO/+N group and 5027 in the CPEO/–N group. The site of the deletion was also similar in the two clinical groups (Fig. 4B). The so-called ‘common deletion’ (from nucleotide 8482 to 13 460) was present in a similar proportion of patients from both clinical groups: in 31% (9/29) CPEO/+N patients and in 32% (13/40) CPEO/–N patients. The similarity of the deletion location in the two clinical groups allowed us to quantify the amount of residual normal mtDNA by the amplification of a mtDNA region constantly included in the deletion (see ‘Methods’ section). The amount of normal mtDNA did not significantly differ between CPEO/+N or CPEO/–N patients, in muscle, blood, urinary or buccal cells (data not shown).
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The presence and proportion of mtDNA deletion was analysed in 63 muscle DNA samples (27 and 36 from CPEO/+N and CPEO/–N patients, respectively), in 27 blood DNA samples (12 and 15 from CPEO/+N and CPEO/–N patients, respectively), in 15 urinary cells DNA samples (7 and 8 for CPEO/+N and CPEO/–N patients, respectively), and in 10 buccal cells DNA samples (5 and 5 for CPEO/+N and CPEO/–N patients, respectively). Using a PCR-based analysis, we could determine the presence of deletion but not if it was included in a more complex rearrangement associating duplication and deletion. The mere presence of the mtDNA deletion in blood was significantly associated with the CPEO/+N phenotype (83% positive blood DNA samples versus 33% in the CPEO/–N group, P = 0.03). The same trend was observed in other samples but the difference did not reach statistical significance. The mtDNA deletion was present in 86% urinary cells DNA samples from CPEO/+N patients versus 62% from CPEO/–N patients. It was present in 80% buccal cells DNA samples from CPEO/+N patients versus 60% from CPEO/–N patients. The median of the mtDNA deletion proportion in muscle, blood, urinary and buccal cells of CPEO/+N patients was higher than in the same tissues of CPEO/–N patients (Fig. 5). That difference was highly significant in DNA samples from blood (11.0% in samples from CPEO/+N patients versus 0.0% in samples from CPEO/–N patients, P = 0.007) but not in DNA samples from muscle (62.3% in samples from CPEO/+N patients versus 52.5% in samples from CPEO/–N patients, P = 0.22) as already reported (Zeviani et al, 1988
), nor from urinary or buccal cells (Fig. 5). As age may modify the proportion of mtDNA deletion (Larsson et al, 1990), we verified that there was no significant difference in the age at blood sampling between the two clinical groups (median 34,0 years in CPEO/+N patients versus 43,0 years in CPEO/–N patients, P = 0.20).
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Discussion |
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This study is the first to establish the natural history of CPEO associated with mtDNA deletion in a large cohort of patients. It has the immediate interest to draw an overall progression pattern that might serve for comparison purpose in the prospect of therapeutic trials. It may also help the patients’ care by improving the prediction of their disease progression, which ranges from mild, predominantly ocular, disease to very severe multi-organs involvement (Butler and Gadoth, 1976
; Berenberg et al., 1977; Holt et al, 1989; Moraes et al, 1989).
We considered that the outcome of brain functions was the most important parameter for the patients’ prognosis. We therefore defined a severe clinical group (CPEO/+N) including the patients with central nervous system involvement and manifestations from the inner ear and/or retina. These latter were considered a risk factor for developing brain symptoms on the basis that the onset of the mtDNA deletion is a unique mutational event occurring early in embryogenesis (Shanske et al, 1990; Zeviani et al, 1990) and that tissues with close embryological origin, such as brain, inner ear and retina, have a high risk to share the same mutation. The link between brain and sensorial defect was shown by the presence of deafness and/or retinitis pigmentosa in 73% (11/15) of the patients with central nervous system involvement. Brain imaging further emphasized the link between sensorial organs and brain involvement by showing anomalies in 5/6 CPEO/+N patients with a sensorial defect but no cerebral symptom and in none of 12 CPEO/–N patients (P < 0.001). The observed anomalies in the CPEO/+N patients were abnormal central white matter signal (61.5%), basal ganglia calcifications (31%), cortical and/or cerebellar atrophy (46%). The proposal of deafness as a risk factor for cerebral involvement fitted with the natural history of CPEO/+N patients as, despite its obviously delayed recognition, deafness still occurred earlier than brain symptoms (Fig. 2). This anteriority could not be established for retinal degeneration, the onset of which could not be precisely ascertained.
By excluding heart conduction defect of the criteria of inclusion into the CPEO/+N group, we did not follow previous classification of KSS, the model of severe form of chronic external ophthalmoplegia (Berenberg et al, 1977). In this report, heart conduction defect was similarly encountered in patients with cerebral symptoms (7/15, 47%) and without cerebral symptoms (23/54, 43%) showing its high frequency in diseases associated with mtDNA deletion, whatever their associated neurological signs. Clinical involvement of heart conduction tissue cannot be considered a bad prognosis indicator in itself as it is a treatable disorder. It was not considered a risk factor for brain involvement because of its embryological origin different from brain.
Analysis of the clinical outcome of the patients validated our classification as it showed that the CPEO/+N group had a significantly more severe outcome with respect to life expectancy, as well as tissue distribution and rate of progression of the diverse signs. Analysis of the patients at the beginning of their disease showed age at onset as an efficient predictive parameter with a maximal risk to develop a CPEO/+N phenotype when the disease onset was before 9 years of age and a minimal one when onset was after 20 years of age according to the 5% CI of age at onset in both groups. Supplementary clinical arguments for a CPEO/+N progression could be brought by an initial symptom different from CPEO/–N or by the presence of inner ear, retina or brain involvement. These latter defects may still be clinically silent and have therefore to be searched for by audiogram, electroretinogram or brain imaging. Metabolic investigations could theoretically distinguish different degree of severity but we had too few evaluations to be able to draw any conclusion. Molecular investigations were previously considered unhelpful with respect to prognostic evaluation. However, we showed that both the presence and the actual proportion of mtDNA deletion in blood were significantly associated with the CPEO/+N phenotype. Although showing the same trend, data from urinary or buccal cells samples were available in too few patients to allow a firm conclusion on their significance.
The difference in severity between CPEO/+N and CPEO/–N patients could be essentially explained by their difference in mutation load. Indeed the proportion of the mtDNA deletion in the diverse tissues of CPEO/+N patients was systematically higher than in CPEO/–N similar samples. Furthermore, both groups looked identical with respect to their progressive and parallel involvement of non-embryologically linked organs, and the similarity of size and location of the mtDNA deletions. However, this hypothesis cannot take into account the fact that the mere presence of the mtDNA deletion in blood, not taking into account its proportion, is significantly associated with the CPEO/+N phenotype. Although this could be due to a more efficient segregation of a lower proportion of the mtDNA deletion in the blood of CPEO/–N patients, this possibility has never been demonstrated (Mcshane et al, 1991). Furthermore, in our series, we did not find correlation between the mtDNA deletion proportion in blood and age at blood sampling going from 23 to 60 years of age (25 patients). Significant influence of the genetic background may probably exist but is very difficult to test.
In conclusion, whether arbitrary or corresponding to different specific entities, the definition of two clinical groups according to the severity of progression has obvious practical interest. The severe phenotype, labelled CPEO/+N, is characterized by a high incidence of brain symptoms in the context of a multi-organ disease, relatively rapid progression of each organ involvement and reduced life expectancy. An early onset (below 9 years of age) and high proportion of the mtDNA deletion in blood are predictive of CPEO/+N progression. More systematic metabolic investigations and molecular analysis of urinary and buccal cells mtDNA are needed to assess the significance of these parameters in the prognostic evaluation of patients with chronic ophthalmoplegia due to mtDNA deletions.
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Acknowledgements |
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This work has been supported by grants from the AFM (Association Française contre les Myopathies). K A is the recipient of a post-doctoral fellowship from AP-HP (Assistance Publique-Hôpitaux de Paris) and FRM (Fondation pour la Recherche Médicale). We wish to thank all the physicians who contributed to the clinical data and to the collection of samples, in particular Dr Menard (Rennes), Dr Walters (Saint-Denis de la Réunion), Dr Turquet (Saint-Denis de la Réunion) and Dr Goldenberg (Rouen). We thank Dr Nigel Clarke for his most useful comments on the manuscript.
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References |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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Auré K, Fayet G, Leroy JP, Lacène E, Romero NB, Lombès A. (2006) Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation. Brain 129:1249–59.
Bastiaensen LAK, Joosten EM, De Rooij JAM, Hommes OR, Stadhouders AM, Jaspar HHJ, et al. (1978) Ophthalmoplegia-plus, a real nosological entity. Acta Neurol Scand 58:9–34.[Web of Science][Medline]
Berenberg RA, Pellock JM, DiMauro S, Schotland DL, Bonilla E, Eastwood A, et al. (1977) Lumping or splitting? "Ophthalmoplegia-plus" or Kearns-Sayre syndrome? Ann Neurol 1:37–54.[CrossRef][Web of Science][Medline]
Bernes SM, Bacino C, Prezant TR, Pearson MA, Wood TS, Fournier P, et al. (1993) Identical mitochondrial DNA deletion in mother with progressive external ophtalmoplegia and son with Pearson marrow-pancreas syndrome. J Pediatrics 123:598–602.[CrossRef][Web of Science][Medline]
Brockington M, Alsanjari N, Sweeney MG, Morgan-Hughes JA, Scaravilli F, Harding AE. (1995) Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study. J Neurol Sci 131:78–87.[CrossRef][Web of Science][Medline]
Butler IJ and Gadoth N. (1976) Kearns-Sayre syndrome. A review of a multisystem disorder of children and young adults. Arch Intern Med 136:1290–3.
Cheng G, Litchenberg WH, Cole GJ, Mikawa T, Thompson RP, Gourdie RG. (1999) Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage. Development 126:5041–9.[Abstract]
Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, et al. (2000) The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48:188–93.[CrossRef][Web of Science][Medline]
Drachman DA. (1968) Ophthalmoplegia plus: the neurodegenerative disorders associated with progressive external ophthalmoplegia. Arch Neurol 18:654–74.
Gerbitz KD, Obermaier-Kusser B, Zierz S, Pongratz D, Müller-Höcker J, Lestienne P. (1990) Mitochondrial myopathies: divergence of genetic deletions, biochemical defects and the clinical syndromes. J Neurol 237:5–10.[CrossRef][Web of Science][Medline]
Hammans SR, Sweeney MG, Wicks DAG, Morgan-Hughes JA, Harding AE. (1992) A molecular genetic study of focal histochemical defects in mitochondrial encephalomyopathies. Brain 115:343–65.
Holt IJ, Harding AE, Cooper JM, Schapira AHV, Toscano A, Clark JB, et al. (1989) Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol 26:699–708.[CrossRef][Web of Science][Medline]
Holt IJ, Harding AE, Morgan-Hughes JA. (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–9.[CrossRef][Medline]
Hurko O, Johns DR, Rutledge SL, Stine OC, Peterson PL, Miller NR, et al. (1990) Heteroplasmy in chronic external ophthalmoplegia: clinical and molecular observations. Pediatr Res 28:542–8.[CrossRef][Web of Science][Medline]
Kearns TP and Sayre GP. (1958) Retinitis pigmentosa, external ophthalmoplegia and complete heart block. Unusual syndrome with histologic study in one of two cases. Arch Ophthalmol (Chicago) 60:280.
Lacbawan F, Tifft CJ, Luban NL, Schmandt SM, Guerrera M, Weinstein S, et al. (2000) Clinical heterogeneity in mitochondrial DNA deletion disorders: a diagnostic challenge of Pearson syndrome. Am J Med Genet 95:266–8.[CrossRef][Web of Science][Medline]
Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulinius M. (1990) Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediatr Res 28:131–6.[Web of Science][Medline]
Manfredi G, Vu T, Bonilla E, Schon EA, DiMauro S, Arnaudo E, et al. (1997) Association of myopathy with large-scale mitochondrial DNA duplications and deletions: which is pathogenic? Ann Neurol 42:180–8.[CrossRef][Web of Science][Medline]
McShane MA, Hammans SR, Sweeney M, Holt IJ, Beattie TJ, Brett EM, et al. (1991) Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet 48:39–42.[Web of Science][Medline]
Moraes CT, DiMauro S, Zeviani M, Lombès A, Shanske S, Miranda A, et al. (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320:1293–9.[Abstract]
Odoardi F, Rana M, Broccolini A, Mirabella M, Modoni A, D’Amico A, et al. (2003) Pathogenic role of mtDNA duplications in mitochondrial diseases associated with mtDNA deletions. Am J Med Genet A 118:247–54.[Medline]
Oldfors A, Larsson NG, Holme E, Tulinius M, Kadenbach B, Droste M. (1992) Mitochondrial DNA deletions and cytochrome c oxidase deficiency in muscle fibres. J Neurol Sci 110:169–77.[CrossRef][Web of Science][Medline]
Pearson HA, Lobel JS, Kocoshis SA, Naiman JW, Windmuller J, Lammi AT, et al. (1979) A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatrics 95:976–84.[CrossRef][Web of Science][Medline]
Poulton J, Deadman ME, Ramacharan S, Gardiner RM. (1991) Germ-line deletions of mtDNA in mitochondrial myopathy. Am J Hum Genet 48:649–53.[Web of Science][Medline]
Poulton J, Morten KJ, Weber K, Brown GK, Bindoff L. (1994) Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome? Hum Mol Genet 3:947–51.
Remes AM, Majamaa-Voltti K, Karppa M, Moilanen JS, Uimonen S, Helander H, et al. (2005) Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population. Neurology 64:976–81.
Rotig A, Bourgeron T, Chretien D, Rustin P, Munnich A. (1995) Spectrum of mitochondrial DNA rearrangements in the Pearson marrow-pancreas syndrome. Hum Mol Genet 4:1327–30.
Sciacco M, Bonilla E, Schon EA, DiMauro S, Moraes CT. (1994) Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum Mol Genet 3:13–9.
Shanske S, Moraes CT, Lombès A, Miranda AF, Bonilla E, Lewis P, et al. (1990) Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome. Neurology 40:24–8.
Shanske S, Tang Y, Hirano M, Nishigaki Y, Tanji K, Bonilla E, et al. (2002) Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with pearson syndrome. Am J Hum Genet 71:679–83.[CrossRef][Web of Science][Medline]
Shy GM, Silberberg DH, Appel SH, Mishkin MM, Godfrey EH. (1967) A generalized disorder of nervous system, skeletal muscle and heart resembling Refsum's disease and Hurler's syndrome. I. Clinical, pathologic and biochemical characteristics. Am J Med 42:163–8.[CrossRef][Web of Science][Medline]
Yamamoto M, Clemens PR, Engel AG. (1991) Mitochondrial DNA deletions in mitochondrial cytopathies: observations in 19 patients. Neurology 41:1822–8.
Zeviani M, Gellera C, Pannacci M, Uziel G, Prelle A, Servidei S, et al. (1990) Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies. Ann Neurol 28:94–7.[CrossRef][Web of Science][Medline]
Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, et al. (1988) Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–46.
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