Journal of Inherited Metabolic Disease, Apr 1, 2011
Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, curr... more Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, currently no effective remedy for mitochondrial disorders is available. One particular strategy in mitochondrial medicine presently under study is metabolic manipulation. This approach is aimed at counteracting the deranged cell biological homeostasis caused by mitochondrial dysfunction, using dietary modifications or small molecule therapy. Cell biological alterations caused by mitochondrial dysfunction include increased reactive oxygen species production, enhanced lipid peroxidation and altered cellular calcium homeostasis. This review covers the five principles of metabolic manipulation: (1) prevention of oxidative damage by reactive oxygen species, (2) amelioration of lipid peroxidation, (3) correction of altered membrane potential, (4) restoration of calcium homeostasis, and (5) transcription regulation interference. We hypothesize that a combination of compounds targeting different metabolic pathways will abolish cellular disturbance arising as a consequences of mitochondrial dysfunction, and thereby improve or stabilize clinical features. However, only a handful of compounds have reached efficacy testing in mammals, and it remains unknown to what extent metabolic manipulation will affect the whole organism. Until a potent remedy is found, patients will remain dependent on supportive, not curative, interventions. Ca 2+ Calcium CoQ10 Co-enzyme Q10 CPEO Chronic progressive external ophthalmoplegia CPT2 Carnitine palmitoyltransferase II COX Cytochrome c oxidase ER Endoplasmic reticulum FA Friedreich ataxia IMM Inner mitochondrial membrane LHON Leber hereditary optic neuropathy MitoQ Mitoquinone MMP Mitochondrial membrane potential MnSOD2 Manganese-super oxide dismutase 2 MPP Mitochondria penetrating peptide mtDNA Mitochondrial DNA NAD + Nicotinamide adenine dinucleotide NADH Nicotinamide adenine dinucleotide reduced form NARP neuropathy, ataxia and retinitis pigmentosa OXPHOS Oxidative phosphorylation PBN Alpha-phenyl N-tertiary-butyl nitrone PDHC Pyruvate dehydrogenase complex PGC1α Peroxisome proliferator-activated receptor gamma coactivator-1 alpha PPARγ Peroxisome proliferator-activated receptor gamma rAAV-SOD2 Recombinant adeno-associated virus (rAAV) containing the SOD2 gene ROS Reactive oxygen species Communicated by: John Christodoulou References to electronic databases: e.g., OMIM disorder/gene accession number(s) OMIM #606426 Co-enzyme Q biosynthesis defects;
Research of patients with defects in cellular energy metabolism (mitochondrial disease) has led t... more Research of patients with defects in cellular energy metabolism (mitochondrial disease) has led to a better understanding of mitochondrial biology in health and disease. The obtained knowledge is of increasing importance for physicians of all medical disciplines. It assists in enabling the development of rational treatment strategies for diseases or conditions caused by mitochondrial dysfunction. The still frequently used classical interventions with vitamins or cofactors are only beneficial in some rare mitochondrial disease conditions, like coenzyme Q biosynthesis defects. For that reason alternative strategies to cor-rect disturbed energy metabolism have to be developed. New approaches in this direction include nutrition and exercise therapies, alternative gene expression, enzyme-replacement, scavenging of potentially toxic compounds and modulating cell signalling. The effect of some of these interventions has already been explored in humans whilst others are still at the level of single cell research. We review the state of the art of the development of mitochondrial treatment strategies and discuss what steps need to be taken to efficiently approach the huge burden of disease caused by dysfunctional mitochondria.
Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, curr... more Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, currently no effective remedy for mitochondrial disorders is available. One particular strategy in mitochondrial medicine presently under study is metabolic manipulation. This approach is aimed at counteracting the deranged cell biological homeostasis caused by mitochondrial dysfunction, using dietary modifications or small molecule therapy. Cell biological alterations caused by mitochondrial dysfunction include increased reactive oxygen species production, enhanced lipid peroxidation and altered cellular calcium homeostasis. This review covers the five principles of metabolic manipulation: (1) prevention of oxidative damage by reactive oxygen species, (2) amelioration of lipid peroxidation, (3) correction of altered membrane potential, (4) restoration of calcium homeostasis, and (5) transcription regulation interference. We hypothesize that a combination of compounds targeting different metabolic pathways will abolish cellular disturbance arising as a consequences of mitochondrial dysfunction, and thereby improve or stabilize clinical features. However, only a handful of compounds have reached efficacy testing in mammals, and it remains unknown to what extent metabolic manipulation will affect the whole organism. Until a potent remedy is found, patients will remain dependent on supportive, not curative, interventions. Ca 2+ Calcium CoQ10 Co-enzyme Q10 CPEO Chronic progressive external ophthalmoplegia CPT2 Carnitine palmitoyltransferase II COX Cytochrome c oxidase ER Endoplasmic reticulum FA Friedreich ataxia IMM Inner mitochondrial membrane LHON Leber hereditary optic neuropathy MitoQ Mitoquinone MMP Mitochondrial membrane potential MnSOD2 Manganese-super oxide dismutase 2 MPP Mitochondria penetrating peptide mtDNA Mitochondrial DNA NAD + Nicotinamide adenine dinucleotide NADH Nicotinamide adenine dinucleotide reduced form NARP neuropathy, ataxia and retinitis pigmentosa OXPHOS Oxidative phosphorylation PBN Alpha-phenyl N-tertiary-butyl nitrone PDHC Pyruvate dehydrogenase complex PGC1α Peroxisome proliferator-activated receptor gamma coactivator-1 alpha PPARγ Peroxisome proliferator-activated receptor gamma rAAV-SOD2 Recombinant adeno-associated virus (rAAV) containing the SOD2 gene ROS Reactive oxygen species Communicated by: John Christodoulou References to electronic databases: e.g., OMIM disorder/gene accession number(s) OMIM #606426 Co-enzyme Q biosynthesis defects;
Developmental Medicine & Child Neurology, 2013
AimA clinical trial is only as reliable as its outcomes, therefore the careful and systematic sel... more AimA clinical trial is only as reliable as its outcomes, therefore the careful and systematic selection of outcome measures is extremely important. Currently, the selection of outcome measures for clinical trials designed to evaluate new drugs in patients with mitochondrial disorders is inefficient and has not been addressed systematically. Given that meaningful data can be obtained only from trials in which outcomes are assessed using valid instruments, one should first focus on the validation of a set of selected instruments in the target population. The aim of this review is to systematically select a ‘toolbox’ of robust outcome measures that are relevant to all patients.MethodUsing an extensive search of published literature, we systematically compiled a toolbox with outcome measures based on a primary search for possible instruments Subsequently, we reduced this toolbox using strict criteria that were adapted from the United States Food and Drug Administration.ResultsA toolbox ...
More than half of the patients harbouring the m.3243A > G mutation were found to have trouble ... more More than half of the patients harbouring the m.3243A > G mutation were found to have trouble maintaining balance when walking in a recent study by our group. Others demonstrated that these patients had an abnormal gait pattern, as quantified by gait analysis. Gait analysis is an emerging method to quantify subtle changes in walking pattern, also during therapeutic interventions. Therefore, we aimed to test the reliability and reproducibility of gait analysis and select the most suitable protocol for this group of patients using a GAITRite electronic walkway. Four different protocols were tested: normal walking, dual task, post exercise and after a ten minutes of rest. In total 36 patients with the m.3243A > G mutation and 50 healthy controls were enrolled in this study. Overall high intra class correlation coefficients were found in all experimental conditions for both patients and healthy controls indicating good reproducibility. Marked differences in gait between patients a...
Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mor... more Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mortality. Two dimensional speckle tracking echocardiography (2DSTE) can be used to quantify myocardial deformation. Here, we aimed to determine the usefulness of 2DSTE in detecting and monitoring subtle changes in myocardial dysfunction in carriers of the 3243A>G mutation in mitochondrial DNA. In this retrospective pilot study, 30 symptomatic and asymptomatic carriers of the mitochondrial 3243A>G mutation of whom two subsequent echocardiograms were available were included. We measured longitudinal, circumferential and radial strain using 2DSTE. Results were compared to published reference values. Speckle tracking was feasible in 90 % of the patients for longitudinal strain. Circumferential and radial strain showed low face validity (low number of images with sufficient quality; suboptimal tracking) and were therefore rejected for further analysis. Global longitudinal strain showed go...
Feasible, sensitive and clinically relevant outcome measures are of extreme importance when desig... more Feasible, sensitive and clinically relevant outcome measures are of extreme importance when designing clinical trials. For paediatric mitochondrial disease, no robust end point has been described to date. The aim of this study was to select the domains of daily physical activity, which can be measured by 3D accelerometry, that could serve as sensitive end points in future clinical trials in children with mitochondrial disorders. In this exploratory observational study, 17 patients with mitochondrial disease and 16 age-and sex-matched controls wore 3D accelerometers at the upper leg, upper arm, lower arm and chest during one weekend. Using the raw data obtained by the accelerometers, we calculated the following outcome measures: (1) average amount of counts per hour the sensors were worn; (2) the maximal intensity; (3) the largest area under the curve during 30 min and (4) categorized activities lying, standing or being dynamically active. Measuring physical activity during the whole weekend was practically feasible in all participants. We found good face validity by visually correlating the validation videos and activity diaries to the accelerometer data-graphs. Patients with mitochondrial disorders had significantly lower peak intensity and were resting more, compared to their age-and sex-matched peers. Finally, we suggest domains of physical activity that could be included when measuring daily physical activity in children with mitochondrial disorders, preferably using more user-friendly devices. These include peak activity parameters for the arms (all patients) and legs (ambulatory patients). We recommend using or developing devices that measure these domains of physical activity in future clinical studies.
We developed the first user-friendly, semi-quantitative, and quick-to-perform Radboud Centre for ... more We developed the first user-friendly, semi-quantitative, and quick-to-perform Radboud Centre for Mitochondrial Medicine Pediatric MRI score (RCMM-PMRIS), focusing on the six most commonly described neuroimaging abnormalities in the literature. The RCMM-PMRIS was validated through individual review of 30 sets of brain MRI studies in 24 patients with genetically confirmed mitochondrial disorders by six raters. The application of RCMM-PMRIS can help to define the extent of the brain involvement and therefore to assess the radiological mitochondrial disease severity, to monitor disease progression and consequently to act as an outcome measure for treatment effects in patients with mitochondrial disease.
Journal of inherited metabolic disease, Sep 9, 2016
There is an urgent need for reliable and universally applicable outcome measures for children wit... more There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6-16 years) from five different expert centres from four different continents were evaluated in this study. The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three facto...
Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243... more Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243A > G mutation reflecting being one of the most common mutations in mitochondrial DNA. Previous studies showed little relationship between mitochondrial genetics and disease manifestation. Relationship between genotype and disease manifestation with patient reported quality of life and other patient reported outcomes is still unexplored. Seventy-two out of the 122 invited adult patients with m.3243A > G mutation completed online standardized questionnaires on quality of life, functional impairment, fatigue and mental health as assessed by the RAND-SF36, the Sickness Impact Profile (SIP), the Checklist Individual Strength (CIS) and the Hospital Anxiety and Depression scale (HADS). Data were related to clinical manifestation reflected by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score and heteroplasmy levels of the mutation in urine epithelial cells. Patients reported i...
This review presents our current understanding of the pathophysiology and potential treatment str... more This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA-encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole-exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient-derived fibroblasts, and how this information can be used for the rational design of small-molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.
The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neu... more The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neuromuscular disease. Since this submaximal endurance test is not feasible for non-ambulatory patients, the motor-assisted 6-minute cycling test (a6MCT) was developed. Nineteen children with neuromuscular disorders and children with OXPHOS-dysfunction performed the a6MCT and the 6MWT to explore feasibility and construct validity. Test-retest reproducibility was evaluated within 3 weeks. The assisted 6-minute cycling test was feasible in 90% and 78% of the patients with a neuromuscular disorder and OXPHOS-dysfunction, respectively. The a6MCT for legs correlated with the 6MWT in both patient groups. The assisted 6-minute cycling showed good reproducibility for both legs and arms. This exploratory study indicates that the assisted 6-minute cycling test is a promising outcome measure for patients with a neuromuscular disorder and patients with OXPHOS-dysfunction. This article is protected by c...
In this observational cohort study, we examined the prognostic value of growth and differentiatio... more In this observational cohort study, we examined the prognostic value of growth and differentiation factor 15 (GDF15) in indicating and monitoring general mitochondrial disease severity and progression in adult carriers of the m.3243A>G mutation. Ninety-seven adult carriers of the m.3243A>G mutation were included in this study. The Newcastle mitochondrial disease adult scale was used for rating mitochondrial disease severity. In parallel, blood was drawn for GDF15 analysis by ELISA. Forty-nine carriers were included in a follow-up study. In a small subset of subjects of whom an echocardiogram was available from general patient care, myocardial deformation was assessed using two-dimensional speckle-tracking strain analysis. A moderate positive correlation was found between the concentration of GDF15 and disease severity (r ¼ 0.59; p < 0.001). The concentration of serum GDF15 was higher in m.3243A>G carriers with diabetes mellitus, cardiomyopathy, and renal abnormalities. After a 2-year follow-up, no significant correlation was found between the change in disease severity and the change in the concentration of GDF15 or between the GDF15 level at the first assessment and the change in disease severity. In the subcohort of patients of whom an echocardiogram was available, the concentration of GDF15 correlated moderately to longitudinal global strain (r ¼ 0.55; p ¼ 0.006; n ¼ 23) but not to circumferential or radial strain. Our results indicate that serum GDF15 is not a strong surrogate marker for general mitochondrial disease severity. Its value in indicating myocardial deformation should be confirmed in a prospective longitudinal study.
To determine the value of fibroblast growth factor 21 (FGF21), a recently discovered biomarker fo... more To determine the value of fibroblast growth factor 21 (FGF21), a recently discovered biomarker for mitochondrial disease, in predicting clinical disease severity and disease progression in adult carriers of the m.3243A>G mutation. In the context of a national inventory, the heteroplasmy levels of the m.3243A>G mutation were measured in leukocytes and urinary epithelial cells. The Newcastle Mitochondrial Disease Adult Scale score was determined and blood was drawn for measuring FGF21 concentration. Twenty-five of the included initial patients studied were then selected randomly for a follow-up study. This prognostic study included 99 adult carriers of the m.3243A>G mutation. Our analysis revealed a moderate, significant correlation between FGF21 concentration and disease severity (r = 0.49; p = <0.001). No significant correlations were found between disease severity and the heteroplasmy percentage determined in urinary epithelial cells or the heteroplasmy percentage deter...
Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves ... more Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new
The m.3243A>G is the most prevalent pathogenic mtDNA mutation but little is known about its inher... more The m.3243A>G is the most prevalent pathogenic mtDNA mutation but little is known about its inheritance. We studied 34 families containing 56 motherchild relations and 82 intersibling relations to investigate its transmission. We found a significant correlation between mother and child heteroplasmy levels (r ¼ 0.679, p < 0.001). In mothers with a heteroplasmy level of below 25% we found 30% offspring without detectable mutation, while in mothers with a heteroplasmy level of above 25%, 100% of the offspring showed the m.3243A>G mutation. Heteroplasmy levels between siblings also correlated (r ¼ 0.512, p < 0.001), but had limited extra predictive value because of outliers. These new data on inheritance of the m.3243A>G mutation might be of value in counseling patients and preventing transmission of the mutation.
The development of neurologic disease is a complex and multi-faceted process. Several factors, su... more The development of neurologic disease is a complex and multi-faceted process. Several factors, such as physiology, environment and genetics may play key roles in the manifestation of the associated illnesses. During the past decades, it has become clear that, at the cellular level, mitochondria function as more than "just" an energy source for our cells and plays a significant role in such aspects as neuronal development, maintenance and degeneration. Malfunctions in mitochondrial respiration and ATP production may prove disastrous for our cells and neurons, ultimately resulting in apoptosis, neurodegeneration and consequently, neurodegenerative diseases.
Journal of Inherited Metabolic Disease, Apr 1, 2011
Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, curr... more Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, currently no effective remedy for mitochondrial disorders is available. One particular strategy in mitochondrial medicine presently under study is metabolic manipulation. This approach is aimed at counteracting the deranged cell biological homeostasis caused by mitochondrial dysfunction, using dietary modifications or small molecule therapy. Cell biological alterations caused by mitochondrial dysfunction include increased reactive oxygen species production, enhanced lipid peroxidation and altered cellular calcium homeostasis. This review covers the five principles of metabolic manipulation: (1) prevention of oxidative damage by reactive oxygen species, (2) amelioration of lipid peroxidation, (3) correction of altered membrane potential, (4) restoration of calcium homeostasis, and (5) transcription regulation interference. We hypothesize that a combination of compounds targeting different metabolic pathways will abolish cellular disturbance arising as a consequences of mitochondrial dysfunction, and thereby improve or stabilize clinical features. However, only a handful of compounds have reached efficacy testing in mammals, and it remains unknown to what extent metabolic manipulation will affect the whole organism. Until a potent remedy is found, patients will remain dependent on supportive, not curative, interventions. Ca 2+ Calcium CoQ10 Co-enzyme Q10 CPEO Chronic progressive external ophthalmoplegia CPT2 Carnitine palmitoyltransferase II COX Cytochrome c oxidase ER Endoplasmic reticulum FA Friedreich ataxia IMM Inner mitochondrial membrane LHON Leber hereditary optic neuropathy MitoQ Mitoquinone MMP Mitochondrial membrane potential MnSOD2 Manganese-super oxide dismutase 2 MPP Mitochondria penetrating peptide mtDNA Mitochondrial DNA NAD + Nicotinamide adenine dinucleotide NADH Nicotinamide adenine dinucleotide reduced form NARP neuropathy, ataxia and retinitis pigmentosa OXPHOS Oxidative phosphorylation PBN Alpha-phenyl N-tertiary-butyl nitrone PDHC Pyruvate dehydrogenase complex PGC1α Peroxisome proliferator-activated receptor gamma coactivator-1 alpha PPARγ Peroxisome proliferator-activated receptor gamma rAAV-SOD2 Recombinant adeno-associated virus (rAAV) containing the SOD2 gene ROS Reactive oxygen species Communicated by: John Christodoulou References to electronic databases: e.g., OMIM disorder/gene accession number(s) OMIM #606426 Co-enzyme Q biosynthesis defects;
Research of patients with defects in cellular energy metabolism (mitochondrial disease) has led t... more Research of patients with defects in cellular energy metabolism (mitochondrial disease) has led to a better understanding of mitochondrial biology in health and disease. The obtained knowledge is of increasing importance for physicians of all medical disciplines. It assists in enabling the development of rational treatment strategies for diseases or conditions caused by mitochondrial dysfunction. The still frequently used classical interventions with vitamins or cofactors are only beneficial in some rare mitochondrial disease conditions, like coenzyme Q biosynthesis defects. For that reason alternative strategies to cor-rect disturbed energy metabolism have to be developed. New approaches in this direction include nutrition and exercise therapies, alternative gene expression, enzyme-replacement, scavenging of potentially toxic compounds and modulating cell signalling. The effect of some of these interventions has already been explored in humans whilst others are still at the level of single cell research. We review the state of the art of the development of mitochondrial treatment strategies and discuss what steps need to be taken to efficiently approach the huge burden of disease caused by dysfunctional mitochondria.
Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, curr... more Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, currently no effective remedy for mitochondrial disorders is available. One particular strategy in mitochondrial medicine presently under study is metabolic manipulation. This approach is aimed at counteracting the deranged cell biological homeostasis caused by mitochondrial dysfunction, using dietary modifications or small molecule therapy. Cell biological alterations caused by mitochondrial dysfunction include increased reactive oxygen species production, enhanced lipid peroxidation and altered cellular calcium homeostasis. This review covers the five principles of metabolic manipulation: (1) prevention of oxidative damage by reactive oxygen species, (2) amelioration of lipid peroxidation, (3) correction of altered membrane potential, (4) restoration of calcium homeostasis, and (5) transcription regulation interference. We hypothesize that a combination of compounds targeting different metabolic pathways will abolish cellular disturbance arising as a consequences of mitochondrial dysfunction, and thereby improve or stabilize clinical features. However, only a handful of compounds have reached efficacy testing in mammals, and it remains unknown to what extent metabolic manipulation will affect the whole organism. Until a potent remedy is found, patients will remain dependent on supportive, not curative, interventions. Ca 2+ Calcium CoQ10 Co-enzyme Q10 CPEO Chronic progressive external ophthalmoplegia CPT2 Carnitine palmitoyltransferase II COX Cytochrome c oxidase ER Endoplasmic reticulum FA Friedreich ataxia IMM Inner mitochondrial membrane LHON Leber hereditary optic neuropathy MitoQ Mitoquinone MMP Mitochondrial membrane potential MnSOD2 Manganese-super oxide dismutase 2 MPP Mitochondria penetrating peptide mtDNA Mitochondrial DNA NAD + Nicotinamide adenine dinucleotide NADH Nicotinamide adenine dinucleotide reduced form NARP neuropathy, ataxia and retinitis pigmentosa OXPHOS Oxidative phosphorylation PBN Alpha-phenyl N-tertiary-butyl nitrone PDHC Pyruvate dehydrogenase complex PGC1α Peroxisome proliferator-activated receptor gamma coactivator-1 alpha PPARγ Peroxisome proliferator-activated receptor gamma rAAV-SOD2 Recombinant adeno-associated virus (rAAV) containing the SOD2 gene ROS Reactive oxygen species Communicated by: John Christodoulou References to electronic databases: e.g., OMIM disorder/gene accession number(s) OMIM #606426 Co-enzyme Q biosynthesis defects;
Developmental Medicine & Child Neurology, 2013
AimA clinical trial is only as reliable as its outcomes, therefore the careful and systematic sel... more AimA clinical trial is only as reliable as its outcomes, therefore the careful and systematic selection of outcome measures is extremely important. Currently, the selection of outcome measures for clinical trials designed to evaluate new drugs in patients with mitochondrial disorders is inefficient and has not been addressed systematically. Given that meaningful data can be obtained only from trials in which outcomes are assessed using valid instruments, one should first focus on the validation of a set of selected instruments in the target population. The aim of this review is to systematically select a ‘toolbox’ of robust outcome measures that are relevant to all patients.MethodUsing an extensive search of published literature, we systematically compiled a toolbox with outcome measures based on a primary search for possible instruments Subsequently, we reduced this toolbox using strict criteria that were adapted from the United States Food and Drug Administration.ResultsA toolbox ...
More than half of the patients harbouring the m.3243A > G mutation were found to have trouble ... more More than half of the patients harbouring the m.3243A > G mutation were found to have trouble maintaining balance when walking in a recent study by our group. Others demonstrated that these patients had an abnormal gait pattern, as quantified by gait analysis. Gait analysis is an emerging method to quantify subtle changes in walking pattern, also during therapeutic interventions. Therefore, we aimed to test the reliability and reproducibility of gait analysis and select the most suitable protocol for this group of patients using a GAITRite electronic walkway. Four different protocols were tested: normal walking, dual task, post exercise and after a ten minutes of rest. In total 36 patients with the m.3243A > G mutation and 50 healthy controls were enrolled in this study. Overall high intra class correlation coefficients were found in all experimental conditions for both patients and healthy controls indicating good reproducibility. Marked differences in gait between patients a...
Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mor... more Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mortality. Two dimensional speckle tracking echocardiography (2DSTE) can be used to quantify myocardial deformation. Here, we aimed to determine the usefulness of 2DSTE in detecting and monitoring subtle changes in myocardial dysfunction in carriers of the 3243A>G mutation in mitochondrial DNA. In this retrospective pilot study, 30 symptomatic and asymptomatic carriers of the mitochondrial 3243A>G mutation of whom two subsequent echocardiograms were available were included. We measured longitudinal, circumferential and radial strain using 2DSTE. Results were compared to published reference values. Speckle tracking was feasible in 90 % of the patients for longitudinal strain. Circumferential and radial strain showed low face validity (low number of images with sufficient quality; suboptimal tracking) and were therefore rejected for further analysis. Global longitudinal strain showed go...
Feasible, sensitive and clinically relevant outcome measures are of extreme importance when desig... more Feasible, sensitive and clinically relevant outcome measures are of extreme importance when designing clinical trials. For paediatric mitochondrial disease, no robust end point has been described to date. The aim of this study was to select the domains of daily physical activity, which can be measured by 3D accelerometry, that could serve as sensitive end points in future clinical trials in children with mitochondrial disorders. In this exploratory observational study, 17 patients with mitochondrial disease and 16 age-and sex-matched controls wore 3D accelerometers at the upper leg, upper arm, lower arm and chest during one weekend. Using the raw data obtained by the accelerometers, we calculated the following outcome measures: (1) average amount of counts per hour the sensors were worn; (2) the maximal intensity; (3) the largest area under the curve during 30 min and (4) categorized activities lying, standing or being dynamically active. Measuring physical activity during the whole weekend was practically feasible in all participants. We found good face validity by visually correlating the validation videos and activity diaries to the accelerometer data-graphs. Patients with mitochondrial disorders had significantly lower peak intensity and were resting more, compared to their age-and sex-matched peers. Finally, we suggest domains of physical activity that could be included when measuring daily physical activity in children with mitochondrial disorders, preferably using more user-friendly devices. These include peak activity parameters for the arms (all patients) and legs (ambulatory patients). We recommend using or developing devices that measure these domains of physical activity in future clinical studies.
We developed the first user-friendly, semi-quantitative, and quick-to-perform Radboud Centre for ... more We developed the first user-friendly, semi-quantitative, and quick-to-perform Radboud Centre for Mitochondrial Medicine Pediatric MRI score (RCMM-PMRIS), focusing on the six most commonly described neuroimaging abnormalities in the literature. The RCMM-PMRIS was validated through individual review of 30 sets of brain MRI studies in 24 patients with genetically confirmed mitochondrial disorders by six raters. The application of RCMM-PMRIS can help to define the extent of the brain involvement and therefore to assess the radiological mitochondrial disease severity, to monitor disease progression and consequently to act as an outcome measure for treatment effects in patients with mitochondrial disease.
Journal of inherited metabolic disease, Sep 9, 2016
There is an urgent need for reliable and universally applicable outcome measures for children wit... more There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6-16 years) from five different expert centres from four different continents were evaluated in this study. The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three facto...
Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243... more Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243A > G mutation reflecting being one of the most common mutations in mitochondrial DNA. Previous studies showed little relationship between mitochondrial genetics and disease manifestation. Relationship between genotype and disease manifestation with patient reported quality of life and other patient reported outcomes is still unexplored. Seventy-two out of the 122 invited adult patients with m.3243A > G mutation completed online standardized questionnaires on quality of life, functional impairment, fatigue and mental health as assessed by the RAND-SF36, the Sickness Impact Profile (SIP), the Checklist Individual Strength (CIS) and the Hospital Anxiety and Depression scale (HADS). Data were related to clinical manifestation reflected by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score and heteroplasmy levels of the mutation in urine epithelial cells. Patients reported i...
This review presents our current understanding of the pathophysiology and potential treatment str... more This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA-encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole-exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient-derived fibroblasts, and how this information can be used for the rational design of small-molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.
The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neu... more The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neuromuscular disease. Since this submaximal endurance test is not feasible for non-ambulatory patients, the motor-assisted 6-minute cycling test (a6MCT) was developed. Nineteen children with neuromuscular disorders and children with OXPHOS-dysfunction performed the a6MCT and the 6MWT to explore feasibility and construct validity. Test-retest reproducibility was evaluated within 3 weeks. The assisted 6-minute cycling test was feasible in 90% and 78% of the patients with a neuromuscular disorder and OXPHOS-dysfunction, respectively. The a6MCT for legs correlated with the 6MWT in both patient groups. The assisted 6-minute cycling showed good reproducibility for both legs and arms. This exploratory study indicates that the assisted 6-minute cycling test is a promising outcome measure for patients with a neuromuscular disorder and patients with OXPHOS-dysfunction. This article is protected by c...
In this observational cohort study, we examined the prognostic value of growth and differentiatio... more In this observational cohort study, we examined the prognostic value of growth and differentiation factor 15 (GDF15) in indicating and monitoring general mitochondrial disease severity and progression in adult carriers of the m.3243A>G mutation. Ninety-seven adult carriers of the m.3243A>G mutation were included in this study. The Newcastle mitochondrial disease adult scale was used for rating mitochondrial disease severity. In parallel, blood was drawn for GDF15 analysis by ELISA. Forty-nine carriers were included in a follow-up study. In a small subset of subjects of whom an echocardiogram was available from general patient care, myocardial deformation was assessed using two-dimensional speckle-tracking strain analysis. A moderate positive correlation was found between the concentration of GDF15 and disease severity (r ¼ 0.59; p < 0.001). The concentration of serum GDF15 was higher in m.3243A>G carriers with diabetes mellitus, cardiomyopathy, and renal abnormalities. After a 2-year follow-up, no significant correlation was found between the change in disease severity and the change in the concentration of GDF15 or between the GDF15 level at the first assessment and the change in disease severity. In the subcohort of patients of whom an echocardiogram was available, the concentration of GDF15 correlated moderately to longitudinal global strain (r ¼ 0.55; p ¼ 0.006; n ¼ 23) but not to circumferential or radial strain. Our results indicate that serum GDF15 is not a strong surrogate marker for general mitochondrial disease severity. Its value in indicating myocardial deformation should be confirmed in a prospective longitudinal study.
To determine the value of fibroblast growth factor 21 (FGF21), a recently discovered biomarker fo... more To determine the value of fibroblast growth factor 21 (FGF21), a recently discovered biomarker for mitochondrial disease, in predicting clinical disease severity and disease progression in adult carriers of the m.3243A>G mutation. In the context of a national inventory, the heteroplasmy levels of the m.3243A>G mutation were measured in leukocytes and urinary epithelial cells. The Newcastle Mitochondrial Disease Adult Scale score was determined and blood was drawn for measuring FGF21 concentration. Twenty-five of the included initial patients studied were then selected randomly for a follow-up study. This prognostic study included 99 adult carriers of the m.3243A>G mutation. Our analysis revealed a moderate, significant correlation between FGF21 concentration and disease severity (r = 0.49; p = <0.001). No significant correlations were found between disease severity and the heteroplasmy percentage determined in urinary epithelial cells or the heteroplasmy percentage deter...
Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves ... more Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new
The m.3243A>G is the most prevalent pathogenic mtDNA mutation but little is known about its inher... more The m.3243A>G is the most prevalent pathogenic mtDNA mutation but little is known about its inheritance. We studied 34 families containing 56 motherchild relations and 82 intersibling relations to investigate its transmission. We found a significant correlation between mother and child heteroplasmy levels (r ¼ 0.679, p < 0.001). In mothers with a heteroplasmy level of below 25% we found 30% offspring without detectable mutation, while in mothers with a heteroplasmy level of above 25%, 100% of the offspring showed the m.3243A>G mutation. Heteroplasmy levels between siblings also correlated (r ¼ 0.512, p < 0.001), but had limited extra predictive value because of outliers. These new data on inheritance of the m.3243A>G mutation might be of value in counseling patients and preventing transmission of the mutation.
The development of neurologic disease is a complex and multi-faceted process. Several factors, su... more The development of neurologic disease is a complex and multi-faceted process. Several factors, such as physiology, environment and genetics may play key roles in the manifestation of the associated illnesses. During the past decades, it has become clear that, at the cellular level, mitochondria function as more than "just" an energy source for our cells and plays a significant role in such aspects as neuronal development, maintenance and degeneration. Malfunctions in mitochondrial respiration and ATP production may prove disastrous for our cells and neurons, ultimately resulting in apoptosis, neurodegeneration and consequently, neurodegenerative diseases.
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Papers by Saskia Koene