Therapies are finally under way for neuromuscular disorders (NMDs) such as spinal muscular atrophies or muscular dystrophies. However, two pivotal trials for Duchenne muscular dystrophy failed to ...show significant results and have raised questions of feasibility in this field. This scenario is further complicated by the limited cohort sizes in many NMDs, and by variations in standards of care. In this context appropriate modelling of the preclinical approach is of paramount importance. Considerations have to include equivalence of the animal models, respect interspecies differences, and address disease-specific and method-specific hurdles of translation. Three major criteria eventually decide if a drug can be marketed: safety, efficacy, and mechanism of action. For small cohort sizes determining efficacy is challenging and dependent on selection and quality of outcome criteria. Functional measures, imaging, and biomarkers are constantly evolving. They have to be evaluated against a baseline of placebo or natural history which is lacking or incomplete for most NMDs. In addition, the effect size of an experimental drug is difficult to judge from the preclinical data, in particular from data obtained in mice. In this scenario carefully constructed phase 2 trials can inform on the choice of outcome criteria, cohort size, and trial duration of a pivotal trial. Treatment at a preclinical state, targeted natural history studies or run-in phases without treatment can be valuable alternatives. A conundrum in the field is that timelines of drug developers, academics, regulators, and patients are not the same. This may impact negatively on trial design, outcome criteria, patient selection, and may contribute to failure of drugs which have a valuable mechanism of action and safety profile. Based on examples I will outline problems of previous and ongoing trials, try to formulate what could be teachings to the field, and illustrate points of personal opinion.
Summary Background Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone ...in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. Methods In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10–18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov , number NCT01027884. Findings 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (−3·05%p 95% CI −7·08 to 0·97, p=0·134, vs placebo −9·01%p –13·18 to −4·84, p=0·0001; difference 5·96%p 0·16 to 11·76, p=0·044) and ITT populations (−2·57%p –6·68 to 1·54, p=0·215, vs −8·84%p –12·73 to −4·95, p<0·0001; difference 6·27%p 0·61 to 11·93, p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1 . The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight 25% and six 19% of 32 patients; placebo, nine 26% and seven 21% of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight 25% vs four 12% patients). Interpretation Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. Funding Santhera Pharmaceuticals.
•This study contributes to the natural history of DMD, linking the ambulant and non-ambulant phases.•Respiratory measurements, upper limb function, pinch and grip force are reported.•A composite ...score combining respiratory outcomes, upper limb function and strength is explored.
The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5–18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI −7.44,−0.72, p = 0.02 in ambulant; 4.81, 95% CI −6.79,−2.82, p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI −6.48,−4.45, p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI −4.79,3.47, p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force −5.51%, 95% CI −6.54,−4.48, p < 0.001 in ambulant and a slower decline −2.86%; 95% CI −3.29,−2.43, p < 0.001, in non-ambulant; pinch force: −2.66%, 95% CI −3.82,−1.51, p < 0.001 in ambulant and −2.23%, 95% CI −2.92,−1.53, p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.
As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all ...patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters.
Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male.
Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.
Duchenne Muscular Dystrophy (DMD) is a lethal muscle disorder, caused by mutations in the DMD gene and affects approximately 1:5000-6000 male births. In this report, we identified dysregulation of ...members of the Dlk1-Dio3 miRNA cluster in muscle biopsies of the GRMD dog model. Of these, we selected miR-379 for a detailed investigation because its expression is high in the muscle, and is known to be responsive to glucocorticoid, a class of anti-inflammatory drugs commonly used in DMD patients. Bioinformatics analysis predicts that miR-379 targets EIF4G2, a translational factor, which is involved in the control of mitochondrial metabolic maturation. We confirmed in myoblasts that EIF4G2 is a direct target of miR-379, and identified the DAPIT mitochondrial protein as a translational target of EIF4G2. Knocking down DAPIT in skeletal myotubes resulted in reduced ATP synthesis and myogenic differentiation. We also demonstrated that this pathway is GC-responsive since treating mice with dexamethasone resulted in reduced muscle expression of miR-379 and increased expression of EIF4G2 and DAPIT. Furthermore, miR-379 seric level, which is also elevated in the plasma of DMD patients in comparison with age-matched controls, is reduced by GC treatment. Thus, this newly identified pathway may link GC treatment to a mitochondrial response in DMD.
Background: Sleep disordered breathing (SDB) is common in neuromuscular diseases but its relationship to respiratory function is poorly defined. A study was undertaken to identify distinct patterns ...of SDB, to clarify the relationships between SDB and lung and respiratory muscle function, and to identify daytime predictors for SDB at its onset, for SDB with continuous hypercapnic hypoventilation, and for diurnal respiratory failure. Methods: Upright and supine inspiratory vital capacity (IVC, % predicted), maximal inspiratory muscle pressure (Pimax), respiratory drive (P0.1), respiratory muscle effort (P0.1/Pimax), and arterial blood gas tensions were prospectively compared with polysomnography and capnometry (Ptcco2) in 42 patients with primary myopathies. Results: IVC correlated with respiratory muscle function and gas exchange by day and night. SDB evolved in three distinct patterns from REM hypopnoeas, to REM hypopnoeas with REM hypoventilation, to REM/non-REM (continuous) hypoventilation, and preceded diurnal respiratory failure. SDB correlated with IVC and Pimax which yielded highly predictive thresholds for SDB onset (IVC <60%, Pimax <4.5 kPa), SDB with continuous hypoventilation (IVC <40%, Pimax <4.0 kPa), and SDB with diurnal respiratory failure (IVC <25%, Pimax <3.5 kPa). Conclusion: Progressive ventilatory restriction in neuromuscular diseases correlates with respiratory muscle weakness and results in progressive SDB which, by pattern and severity, can be predicted from daytime lung and respiratory muscle function.
Relative and absolute muscle mass and muscle strength are used as diagnostic criteria for sarcopenia. We aimed to assess which diagnostic criteria are most associated with physical performance in 180 ...young (18–30 years) and 281 healthy old participants (69–81 years) of the European study MYOAGE. Diagnostic criteria included relative muscle mass (total or appendicular lean mass (ALM) as percentage of body mass), absolute muscle mass (ALM/height squared and total lean mass), knee extension torque, and handgrip strength. Physical performance comprised walking speed, Timed Up and Go test (TUG), and in a subgroup physical fitness. Diagnostic criteria for sarcopenia and physical performance were standardized, and the associations were analyzed using linear regression models stratified by age category, with adjustments for age, gender, and country. In old participants, relative muscle mass was associated with faster walking speed, faster TUG, and higher physical fitness (all
p
< 0.001). Absolute muscle mass was not associated with physical performance. Knee extension torque and handgrip strength were associated with faster walking speed (both
p
≤ 0.003). Knee extension torque was associated with TUG (
p
= 0.001). Knee extension torque and handgrip strength were not associated with physical fitness. In young participants, there were no significant associations between diagnostic criteria for sarcopenia and physical performance, except for a positive association between relative muscle mass and physical fitness (
p
< 0.001). Relative muscle mass, defined as lean mass or ALM percentage, was most associated with physical performance. Absolute muscle mass including ALM/height squared was not associated with physical performance. This should be accounted for when defining sarcopenia.
Abstract Upper limb assessment in non-ambulant patients remains a challenge. We have designed new tools to precisely assess pinch (MyoPinch), grip (MyoGrip), wrist flexion and extension (MyoWrist) ...strength. We have also designed a new tool to assess the ability of patients to produce repetitive flexion/extension movements of wrist and fingers (MoviPlate). We have assessed the feasibility and reliability of these new tools in 30 non-ambulant patients with Duchenne muscular dystrophy and in 30 age-matched male controls. Existing measures, such as Motor Function Measure, Tapping, and the Brooke Upper Extremity Functional Rating Scale were also performed. Results demonstrated that assessments were feasible in nearly all upper limbs tested for MyoGrip, MyoPinch and MoviPlate. The reliability of all tests, including MyoWrist which was not feasible in the patients presenting with contractures, was excellent in patients as in controls. Motor capacities decrease with the number of months spent in the wheelchair. The scores in the tests were partially correlated with each other, and with clinical measures such as vital capacity, Motor Function Measure, functional hand scale and Brooke score. This study validates a panel of upper limb muscle strength and function measures for Duchenne Muscular Dystrophy which can be applied from controls to extremely weak patients.
Summary
Currently used diagnostic measures for sarcopenia utilize different measures of muscle mass, muscle strength, and physical performance. These diagnostic measures associate differently to bone ...mineral density (BMD), as an example of muscle-related clinical outcome. These differences should be taken into account when studying sarcopenia.
Introduction
Diagnostic measures for sarcopenia utilize different measures of muscle mass, muscle strength, and physical performance. To understand differences between these measures, we determined the association with respect to whole body BMD, as an example of muscle-related clinical outcome.
Methods
In the European cross-sectional study MYOAGE, 178 young (18–30 years) and 274 healthy old participants (69–81 years) were recruited. Body composition and BMD were evaluated using dual-energy X-ray densitometry. Diagnostic measures for sarcopenia were composed of lean mass as percentage of body mass, appendicular lean mass (ALM) as percentage of body mass, ALM divided by height squared (ALM/height
2
), knee extension torque, grip strength, walking speed, and Timed Up and Go test (TUG). Linear regression models were stratified for sex and age and adjusted for age and country, and body composition in separate models.
Results
Lean mass and ALM/height
2
were positively associated with BMD (
P
< 0.001). Significance remained in all sex and age subgroups after further adjustment for fat mass, except in old women. Lean mass percentage and ALM percentage were inversely associated with BMD in old women (
P
< 0.001). These inverse associations disappeared after adjustment for body mass. Knee extension torque and handgrip strength were positively associated with BMD in all subgroups (
P
< 0.01), except in old women. Walking speed and TUG were not related to BMD.
Conclusions
The associations between diagnostic measures of sarcopenia and BMD as an example of muscle-related outcome vary widely. Differences between diagnostic measures should be taken into account when studying sarcopenia.
PDF
