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Classifying gait patterns into homogeneous groups could enhance communication among healthcare providers, clinical decision making and clinical trial designs in boys with Duchenne muscular dystrophy (DMD). Sutherland's classification has been developed 40 years ago. Ever since, the state-of-the-art medical care has improved and boys with DMD are now longer ambulatory. Therefore, the gait classification requires an update. The overall aim was to develop an up-to-date, valid DMD gait classification. A total of 137 three-dimensional gait analysis sessions were collected in 30 boys with DMD, aged 4.6-17 years. Three classes were distinguished, which only partly aligned with increasing severity of gait deviations. Apart from the mildly affected pattern, two more severely affected gait patterns were found, namely the tiptoeing pattern and the flexion pattern with distinct anterior pelvic tilt and posterior trunk leaning, which showed most severe deviations at the ankle or at the proximal segments/joints, respectively. The agreement between Sutherland's and the current classification was low, suggesting that gait pathology with the current state-of-the-art medical care has changed. However, overlap between classes, especially between the two more affected classes, highlights the complexity of the continuous gait changes. Therefore, caution is required when classifying individual boys with DMD into classes., (© 2024. The Author(s).)

Respiratory complications are common in spinal muscular atrophy (SMA) and significantly contribute to morbidity and mortality in these patients. Generalized respiratory and bulbar muscle weakness translates into diverse and complex clinical consequences necessitating strict follow-up and specialized care. The natural history of SMA has evolved drastically in recent years as a result of the introduction of novel, disease-modifying therapies. While the impact of these therapies on motor function is well described in literature, its consequence for respiratory management has not been extensively studied. In this review we aim to provide a comprehensive overview of the respiratory morbidities, their follow-up, management, and the impact of novel therapies in SMA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Lagae, Proesmans, Van den Hauwe, Vermeulen, De Waele and Boon.)

Background: A disintegrin and metalloprotease 17 (ADAM17) catalyzes platelet glycoprotein (GP) Ibα ectodomain shedding, thereby releasing glycocalicin in plasma. The spatiotemporal control over the enzyme-substrate interaction and the biological consequences of GPIbα shedding are poorly understood., Objectives: This study aimed to determine the spatiotemporal control over GPIbα shedding by ADAM17., Methods: Transmission electron microscopy with immunogold staining, immunoprecipitation, and quantitative western blotting were used., Results: Immunogold staining showed that all ADAM17 antigen is expressed intracellularly, irrespective of platelet activation. ADAM17 clustered in patches on a tortuous membrane system different from α- and dense granules. Mild activation by platelet adhesion to immobilized fibrinogen did not cause GPIbα shedding, whereas strong and sustained stimulation using thrombin and collagen (analogs) did. Glycocalicin release kinetics was considerably slower than typical hemostasis, starting at 20 minutes and reaching a plateau after 3 hours of strong stimulation. Inhibition of the ADAM17 scissile bond specifically in GPIbα receptors that reside on the platelet's extracellular surface did not prevent shedding, which is in line with the strict intracellular location of ADAM17. Instead, shedding was restricted to a large GPIbα subpopulation that is inaccessible on resting platelets but becomes partially accessible following platelet stimulation. Furthermore, the data show that proteinaceous, water-soluble ADAM17 inhibitors cannot inhibit GPIbα shedding, whereas membrane permeable small molecule ADAM inhibitors can., Conclusion: The data show that platelets harbor 2 distinct GPIbα subpopulations: one that presents at the platelet's surface known for its role in primary hemostasis and one that provides substrate for proteolysis by ADAM17 with kinetics that suggest a role beyond hemostasis., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The aim of this study was to determine the clinimetric properties, i.e., reliability, validity and responsiveness of an instrumented strength assessment in typically developing (TD) children and children with cerebral palsy (CP) and Duchenne muscular dystrophy (DMD). Force (N), torque (Nm) and normalized torque (Nm/kg) were defined for maximal voluntary isometric contractions (MVICs) of the lower limb muscles using a pre-established protocol. Intraclass correlation coefficient (ICC), standard error of measurement (SEM) and minimal detectable change (MDC) of TD children ( n = 14), children with CP ( n = 11) and DMD ( n = 11) were used to evaluate intra-rater reliability for the three cohorts and the inter-rater intersession as well as inter-rater intrasession reliability for TD children. Construct validity was assessed by comparing MVICs in TD children ( n = 28) to children with CP ( n = 26) and to children with DMD ( n = 30), using the Kruskal Wallis and post-hoc Mann-Whitney U tests. Responsiveness was investigated by assessing changes in MVICs following a strength intervention in CP ( n = 26) and a 1 and 2 year follow-up study in DMD ( n = 13 and n = 6, respectively), using the Wilcoxon Signed-Rank test. The overall intra-rater reliability, was classified as good to excellent for 65.1%, moderate for 27.0% and poor for 7.9% of the measures (47.6%, 76.2%, and 66.7% good-excellent; 28.6%, 23.8%, and 33.7% moderate; 23.8%, 0%, and 0% poor in TD, CP, and DMD, respectively), while ICC values for TD children were slightly lower for inter-rater intrasession reliability (38.1% good-excellent, 33.3% moderate and 26.6% poor) and for inter-rater intersession reliability (47.6% good-excellent, 23.8% moderate and 28.6% poor). Children with CP and DMD were significantly weaker than TD children ( p < 0.001) and the majority of these strength differences exceeded the MDC. Children with CP significantly improved strength after training, with changes that exceeded the SEMs, whereas only limited strength decreases over time were observed in the DMD cohort. In conclusion, the investigated instrumented strength assessment was sufficiently reliable to confirm known-group validity for both cohorts and could detect the responsiveness of children with CP after a strength intervention. However, more research is necessary to determine the responsiveness of this assessment in children with DMD regarding their natural decline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Verreydt, Vandekerckhove, Stoop, Peeters, van Tittelboom, Van de Walle, Van den Hauwe, Goemans, De Waele, Van Campenhout, Hanssen and Desloovere.)

Prolonging ambulation is an important treatment goal in children with Duchenne muscular dystrophy (DMD). Three-dimensional gait analysis (3DGA) could provide sensitive parameters to study the efficacy of clinical trials aiming to preserve ambulation. However, quantitative descriptions of the natural history of gait features in DMD are first required. The overall goal was to provide a full delineation of the progressive gait pathology in children with DMD, covering the entire period of ambulation, by performing a so-called mixed cross-sectional longitudinal study. Firstly, to make our results comparable with previous literature, we aimed to cross-sectionally compare 31 predefined gait features between children with DMD and a typically developing (TD) database (1). Secondly, we aimed to explore the longitudinal changes in the 31 predefined gait features in growing boys with DMD using follow-up 3DGA sessions (2). 3DGA-sessions ( n = 124) at self-selected speed were collected in 27 boys with DMD (baseline age: 4.6-15 years). They were repeatedly measured over a varying follow-up period (range: 6 months-5 years). The TD group consisted of 27 children (age: 5.4-15.6 years). Per measurement session, the spatiotemporal parameters, and the kinematic and kinetic waveforms were averaged over the selected gait cycles. From the averaged waveforms, discrete gait features (e.g., maxima and minima) were extracted. Mann-Whitney U tests were performed to cross-sectionally analyze the differences between DMD at baseline and TD (1). Linear mixed effect models were performed to assess the changes in gait features in the same group of children with DMD from both a longitudinal (i.e., increasing time) as well as a cross-sectional perspective (i.e., increasing baseline age) (2). At baseline, the boys with DMD differed from the TD children in 17 gait features. Additionally, 21 gait features evolved longitudinally when following-up the same boys with DMD and 25 gait features presented a significant cross-sectional baseline age-effect. The current study quantitatively described the longitudinal alterations in gait features in boys with DMD, thereby providing detailed insight into how DMD gait deteriorates. Additionally, our results highlight that gait features extracted from 3DGA are promising outcome measures for future clinical trials to quantify the efficacy of novel therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vandekerckhove, Van den Hauwe, De Beukelaer, Stoop, Goudriaan, Delporte, Molenberghs, Van Campenhout, De Waele, Goemans, De Groote and Desloovere.)

Objective: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status., Methods: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments., Results: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (β = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (β = -1.15, p < 0.0001) and IIIB (β = -0.69, p = 0.002)., Interpretation: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117., (© 2020 American Neurological Association.)

Aim: Our aim was to determine if synergy weights and activations are altered in Duchenne muscular dystrophy (DMD) and if these alterations could be linked to muscle weakness., Methods: In 22 children with DMD and 22 typical developing (TD) children of a similar age, surface electromyography (sEMG) of the gluteus medius, rectus femoris (REF), medial hamstrings, tibialis anterior, and medial gastrocnemius (GAS) were recorded during gait. Muscle weakness was assessed with maximal voluntary isometric contractions (MVIC). Synergies were calculated with non-negative matrix factorization. The number of synergies explaining ≥90% of the variance in the sEMG signals (N90), were extracted and grouped with k-means cluster analysis. We verified differences in weights with a Mann-Whitney U test. Statistical non-parametric mapping (Hotelling's T2 test and two-tailed t-test) was used to assess group differences in synergy activations. We used Spearman's rank correlation coefficients and canonical correlation analysis to assess if weakness was related to modifications in weights and activations, respectively., Results: For both groups, average N90 was three. In synergy one, characterized by activity at the beginning of stance, the DMDs showed an increased REF weight (p = 0.001) and decreased GAS weight (p = 0.007). Synergy activations were similar, with only a small difference detected in mid-swing in the combined activations (p<0.001). Weakness was not associated with these differences., Conclusion: Despite the apparent weakness in DMD, synergy weights and activations were similar between the two groups. Our findings are in line with previous research suggesting non-neural alterations have limited influence on muscle synergies., Competing Interests: The authors have declared that no competing interests exist.

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls., Competing Interests: The collaborative Trajectory Analysis Project (cTAP) has received sponsorship from Astellas Pharma (Mitobridge), Catabasis, FibroGen Inc., Italfarmaco SpA, Pfizer Inc., PTC Therapeutics, Roche, Sarepta Therapeutics, Shire plc, Solid Biosciences, Wave Life Sciences, Parent Project Muscular Dystrophy, Charley’s Fund, and CureDuchenne, a founding patient advocacy partner and provider of initial seed funding to cTAP. Physical function testing at Universitaire Ziekenhuizen Leuven was funded by Fonds Spierzieke Kinderen. cTAP was involved in study design, analysis, manuscript preparation, and the decision to publish. James Signorovitch, Gautam Sajeev, Madeline Jenkins, Ibrahima Dieye, Zhiwen Yao, and Intekhab Hossain are employees of Analysis Group, Inc. David Cox and John Landry are employees and shareholders of Eli Lilly and Company. Susan J. Ward has received funding from the study sponsors via the Collaborative Trajectory Analysis Project (cTAP). Brenda Wong, Marleen Van den Hauwe, and Nathalie Goemans have no competing interests to disclose. This does not alter adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

The three-minute walk test (3MWT) and timed function tests (TFTs) (rise from floor, 10 m run, climbing and descending four stairs) are currently used to evaluate functional capacity in young boys with neuromuscular disorders. This study aimed to generate normative data in healthy boys aged 2.5 up to 6 years for these tests and to provide percentile curves according to age and height. The relation between the 3MWT, TFTs and anthropometric variables was investigated. In total 179 boys (mean age: 4.1 y ± 1.0) were evaluated across four age (2.5 years; 3 years; 4 years and 5 years) and three height groups: (<100 cm; 100 to <110 cm and ≥110 cm). Three-minute walk distance (3MWD) increased significantly, from 168.4 m (± 18.8) at 2.5 years to 214.5 m (± 26.1) at 5 years and from 172.6 m (±21.8) for children <100 cm to 212.7 m (±26.2) for children ≥110 cm. TFTs times decreased significantly with age and height. Significant correlations between the anthropometric values, 3MWD and TFTs were found (r(s)= 0.55-0.84; p <0.0001). These normative data and percentile curves provide a useful tool in the assessment of functional capacity in young boys. This study also confirms the association between functional tests and anthropometric values., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Prolonged ambulation is considered important in children with Duchenne muscular dystrophy (DMD). However, previous studies analyzing DMD gait were sensitive to false positive outcomes, caused by uncorrected multiple comparisons, regional focus bias, and inter-component covariance bias. Also, while muscle weakness is often suggested to be the main cause for the altered gait pattern in DMD, this was never verified., Research Question: Our research question was twofold: 1) are we able to confirm the sagittal kinematic and kinetic gait alterations described in a previous review with statistical non-parametric mapping (SnPM)? And 2) are these gait deviations related to lower limb weakness?, Methods: We compared gait kinematics and kinetics of 15 children with DMD and 15 typical developing (TD) children (5-17 years), with a two sample Hotelling's T 2 test and post-hoc two-tailed, two-sample t-test. We used canonical correlation analyses to study the relationship between weakness and altered gait parameters. For all analyses, α-level was corrected for multiple comparisons, resulting in α = 0.005., Results: We only found one of the previously reported kinematic deviations: the children with DMD had an increased knee flexion angle during swing (p = 0.0006). Observed gait deviations that were not reported in the review were an increased hip flexion angle during stance (p = 0.0009) and swing (p = 0.0001), altered combined knee and ankle torques (p = 0.0002), and decreased power absorption during stance (p = 0.0001). No relationships between weakness and these gait deviations were found., Significance: We were not able to replicate the gait deviations in DMD previously reported in literature, thus DMD gait remains undefined. Further, weakness does not seem to be linearly related to altered gait features. The progressive nature of the disease requires larger study populations and longitudinal analyses to gain more insight into DMD gait and its underlying causes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Although prolonged ambulation is considered important in children with Duchenne muscular dystrophy (DMD), articles describing gait deviations in DMD are scarce., Research Question: Therefore, our research questions were the following: 1) what are the most consistently reported spatiotemporal-, kinematic-, kinetic-, and muscle activity deviations in children with DMD in literature, 2) what is the quality of the studies describing these deviations, and 3) is there need for further research?, Methods: We conducted a systematic literature search for studies published before the end of June 2017 in six online databases. We created a data extraction form to define information on materials and methods and on the analyzed gait parameters for each paper included in the review. If enough information was available, we calculated standardized mean differences (SMDs)., Results: The search yielded nine articles, but generalizability was poor. Seventy-nine parameters were analyzed by seven research groups, but they only agreed on a decrease in walking speed (minimal SMD: 1.26), stride length (1.83), step length (1.80), dorsiflexion during swing (1.43), maximal power generation at the hip (0.92), maximal knee extension torque (0.99), maximal dorsiflexion torque (-1.30), and maximal power generation at the ankle (0.92), and an increased knee range of motion (-0.82) in DMD., Significance: In order to keep children with DMD ambulant as long as possible, a clear understanding of their pathological gait pattern is necessary. However, gait deviations in DMD appear not well defined. Previous studies appear to be of an exploratory nature while using predefined gait parameters to assess an undirected null hypothesis. This made them prone to regional focus bias, thereby increasing the chance of a type I error. Therefore, further research is required to define the altered gait pattern in children with DMD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cerebral palsy (CP) and Duchenne muscular dystrophy (DMD) are neuromuscular disorders characterized by muscle weakness. Weakness in CP has neural and non-neural components, whereas in DMD, weakness can be considered as a predominantly non-neural problem. Despite the different underlying causes, weakness is a constraint for the central nervous system when controlling gait. CP demonstrates decreased complexity of motor control during gait from muscle synergy analysis, which is reflected by a higher total variance accounted for by one synergy (tVAF 1 ). However, it remains unclear if weakness directly contributes to higher tVAF 1 in CP, or whether altered tVAF 1 reflects mainly neural impairments. If muscle weakness directly contributes to higher tVAF 1 , then tVAF 1 should also be increased in DMD. To examine the etiology of increased tVAF 1 , muscle activity data of gluteus medius, rectus femoris, medial hamstrings, medial gastrocnemius, and tibialis anterior were measured at self-selected walking speed, and strength data from knee extensors, knee flexors, dorsiflexors and plantar flexors, were analyzed in 15 children with CP [median (IQR) age: 8.9 (2.2)], 15 boys with DMD [8.7 (3.1)], and 15 typical developing (TD) children [8.6 (2.7)]. We computed tVAF 1 from 10 concatenated steps with non-negative matrix factorization, and compared tVAF 1 between the three groups with a Mann-Whiney U -test. Spearman's rank correlation coefficients were used to determine if weakness in specific muscle groups contributed to altered tVAF 1 . No significant differences in tVAF 1 were found between DMD [tVAF 1 : 0.60 (0.07)] and TD children [0.65 (0.07)], while tVAF 1 was significantly higher in CP [(0.74 (0.09)] than in the other groups (both p < 0.005). In CP, weakness in the plantar flexors was related to higher tVAF 1 ( r = -0.72). In DMD, knee extensor weakness related to increased tVAF 1 ( r = -0.50). These results suggest that the non-neural weakness in DMD had limited influence on complexity of motor control during gait and that the higher tVAF 1 in children with CP is mainly related to neural impairments caused by the brain lesion.

Duchenne muscular dystrophy is a rare genetic disorder with life-limiting pathology. Drisapersen induces exon 51 skipping, thereby producing a shorter but functional dystrophin protein. The longest available data are from an open-label extension study (PRO051-02) treating 12 boys with drisapersen (6 mg/kg/week subcutaneously). The median change (range) from baseline to week 177 in six-minute walking distance (6MWD) was 8 (-263, 163) metres. The current analysis aimed to put the results from PRO051-02 in the context of natural progression by comparing the functional trajectory of drisapersen-treated subjects to a matched natural history (NH) cohort, treated by standard of care. Subjects were matched individually by age and 6MWD, as the primary analysis, and by age and rise from floor (RFF), as sensitivity analysis. A total of 75 NH subjects were available for 6MWD analysis, of which matching was possible for 9 ambulant drisapersen-treated subjects. None of the 6 "stable" (baseline 6MWD ≥330 metres) drisapersen-treated subjects lost ambulation vs 4 out of 10 matched NH subjects over a comparable timeframe (~3.4 years), compared with 2 out of 3 ambulant "in decline" drisapersen-treated subjects vs all 6 matched NH subjects. A total of 79 NH subjects were available for RFF analysis. For continuous ambulatory subjects (N = 4), the RFF decline was more pronounced in the NH cohort than in the drisapersen-treated subjects. In conclusion, a comparison of ambulant drisapersen-treated subjects with matched NH subjects showed a difference in functional trajectories over a timeframe of up to 3.4 years in favour of drisapersen., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations., Methods: This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73-80), followed by intermittent dosing (weeks 81-188)., Results: Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored "zero". When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α1-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72., Conclusion: Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort., Trial Registration: ClinicalTrials.gov NCT01910649., Competing Interests: Competing Interests: Nathalie M. Goemans has received funding for trials from Prosensa Therapeutics BV limited to the study costs. Rosamund J. Wilson was an employee of Spica Consultants Ltd, Marlborough, UK, and had a consultancy contract with Prosensa Therapeutics BV. Judith C. van Deutekom, Sjef J. de Kimpe, Afrodite Lourbakos and Giles V. Campion were employees (which includes contribution to patent [applications] and participation in stock-option plans) of Prosensa Therapeutics BV. Judith C. van Deutekom, Sjef J. de Kimpe, Afrodite Lourbakos and Giles V. Campion are employees (which includes participation in stock-option plans) of BioMarin Pharamaceutical Inc. None of the contributing authors listed on this paper were affiliated with GlaxoSmithKline at the time of the study. Már Tulinius, Marleen van den Hauwe, Anna-Karin Kroksmark, and Gunnar Buyse have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between -14 and +9 (mean -0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between -2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Duchenne muscular dystrophy (DMD) is the most common and devastating type of muscular dystrophy worldwide. In this study we have investigated the potential of the combined use of non-invasive near-infrared spectroscopy (NIRS) and surface electromyography (sEMG) to assess contraction-induced changes in oxygenation and myoelectrical activity, respectively in the biceps brachii of eight DMD patients aged 9-12 years and 11 age-matched healthy controls. Muscle tissue oxygenation index (TOI), oxyhemoglobin (HbO2), and sEMG signals were continuously measured during a sustained submaximal contraction of 60% maximal voluntary isometric contraction, and post-exercise recovery period. Compared to controls, DMD subjects showed significantly smaller changes in TOI during the contraction. In addition, during the reoxygenation phase some dynamic parameters extracted from the HbO2 measurements were significantly different between the two groups, some of which were correlated with functional performances on a 6-min walking test. In conclusion, non-invasive continuous monitoring of skeletal muscle oxygenation by NIRS is feasible in young children, and significant differences in contraction-induced deoxygenation and reoxygenation patterns were observed between healthy controls and DMD children.

Introduction: A recent Rasch analysis performed on the Hammersmith Functional Motor Scale-Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items., Methods: We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients., Results: The mean 12-month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar., Conclusions: The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items., (© 2015 Wiley Periodicals, Inc.)

Objective: This study aimed to (1) generate normative data in healthy boys aged 5-12 years for the six-minute walk test (6MWT), an outcome measure currently used in clinical trials in Duchenne muscular dystrophy (DMD), (2) to describe the relation with anthropometric variables and myometry, and (3) to compare our data with published equations., Methods: The 6MWT was conducted in 442 boys according to a standardized protocol, as currently used in clinical trials in DMD. Maximal voluntary isometric contractions for knee flexion and extension were recorded with a hand-held myometer., Results: The 6MWD increased significantly with age, from 478.0 ± 44.1 m at age 5, to 650.0 ± 76.8 m at age 12, with the steepest increase between 5 and 8 years. Age- and height related percentile curves of the 6MWD were developed. Correlations with anthropometric variables were fair to good (age r = 0.60, height r = 0.57, weight r = 0.44). Myometric variables (knee flexors and extensors) showed correlations of 0.46 and 0.50 respectively. When dividing into two age categories (5-8 years, 9-12 years), these magnitudes of correlations only applied to the younger age group. Additionally, predicted values were calculated according to available reference equations (Geiger and Ben Saad), indicating an overestimation by those equations. Finally, the Geiger equation was refitted to our population., Conclusion: The percentile curves according to age and height provide a useful tool in the assessment of ambulatory capacity in boys aged 5 to 12 years. Significant correlations with anthropometric variables and myometry were only found in the 5-8 years age group. The Geiger prediction equation, currently used to assess ambulatory capacity in DMD was refitted to obtain a more accurate prediction model based on a large sample with a homogenous distribution across the age categories 5 to 12 years and applying the methodology as currently used in clinical trials in DMD.

In Duchenne muscular dystrophy (DMD) progressive weakness of respiratory muscles leads to a restrictive pulmonary syndrome that contributes to early morbidity and mortality. Currently no curative treatment exists for DMD. In a Phase II randomized placebo-controlled study (DELPHI) in 21 DMD boys at age 8-16 years, idebenone (450 mg/d) showed trends of efficacy for cardiac and respiratory endpoints. Since the DELPHI study population comprised both glucocorticoid-naïve subjects and glucocorticoid-users, we now report a post-hoc analysis investigating the effects of glucocorticoids and idebenone on markers of respiratory weakness, particularly peak expiratory flow (PEF) percent predicted (PEF%p). Baseline values of PEF%p correlated well with the percent predicted values for maximal inspiratory mouth pressure (MIP%p), forced vital capacity (FVC%p), and forced expired volume in 1 sec (FEV1%p). Baseline PEF%p and FVC%p were significantly higher in patients on concomitant glucocorticoids compared to glucocorticoid-naïve patients. In the latter subgroup, idebenone caused a 8.0 ± 12.1% improvement in PEF%p, whilst patients on placebo declined by -12.3 ± 17.9% (P < 0.05) in the course of the 12 month study. In patients receiving concomitant glucocorticoids, PEF%p remained stable (-0.4 ± 14.6%) in the idebenone group compared to a decline by -6.2 ± 12.4% (P = 0.24) in the placebo group. Idebenone showed a trend for efficacy on FVC%p only in glucocorticoid-naïve patients. Because of the study limitations, these data are exploratory and preclude any firm conclusions. In conclusion, PEF appears to be a sensitive respiratory function parameter that could be a valid and clinically relevant endpoint in intervention studies in DMD. In DELPHI the effect size of idebenone on PEF%p was significantly larger in steroid-naive patients, possibly indicating a maximum treatment effect reached by steroids or steroid-mediated suppression of idebenone's effects. The impact of standard care glucocorticoids on respiratory function will have to be considered in the planning of future interventional trials in DMD., (Copyright © 2012 Wiley Periodicals, Inc.)

In order to understand contemporary natural history of Duchenne muscular dystrophy (DMD), we report 6-minute walk distance (6MWD) and its change over time from a large single centre population of corticosteroid treated DMD boys. Sixty-five boys on daily corticosteroid treatment were identified with a mean (SD) age of 9.5 (2.3) years at first observation. 6MWD was described for 1year age groupings. In addition, changes in 6MWD at 1, 1.5 and 2years (±12weeks) of follow-up were evaluated. The same evaluations were applied to 6MWD data converted to percent predicted values based on the Geiger equation. 6MWD showed an increase from age group 4.5-5.5years to age group 6.5-7.5years, followed by a decline, which became precipitous from 12.5years onwards. From 15.5years, all boys were unable to perform the 6-min test. Changes in 6MWD demonstrated a mean (median, SD) decline of -43 (-14, 90) m at 1year (N=25, mean baseline age 9.5years), -64 (-56, 99) m at 1.5years (N=18, mean baseline age 9.6years), -125 (-106, 139) m at 2years (N=14, mean baseline age 10.0years). Conversion to percent predicted values showed the same pattern of evolution.This study provides data on the ambulatory capacity and its changes over time in a homogenous cohort of 65 DMD boys on daily corticosteroids. The variability, the age-related aspects and the slope of decline of the 6MWD should be considered in the design and interpretation of therapeutic trials in ambulant DMD patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The 6-min walk test (6MWT) assesses functional capacity and has been used as outcome measure in therapeutic studies in childhood neuromuscular disorders. The objectives were to evaluate test-retest reliability of the 6MWT and to generate normative data for healthy boys aged 5-12 years. Ninety boys (mean age 8 years 10 months) were recruited over four age subcategories (5-6, 7-8, 9-10, 11-12 years). Mean 6MWT distance and velocity (±standard deviation) for the total group were 555.5±93 m and 92.6±16.6 m/min. The 6MWT distance increased significantly with age. Test-retest reliability (mean interval 12 days) was very high for the total group (ICC>0.95) and for all age subcategories (ICC>0.80) a moderately high reliability (ICC>0.75) was found from 3 min onwards for each age subcategory. There was a mean difference of 5.2 m between test and retest without systematic bias. The standard error of measurement and smallest detectable difference were 20.7 and 57.4 m, respectively. These findings demonstrate the reliability of the 6MWT in young children, underscore its evolution with age, and indicate that a shorter version of the test is also reliable., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the alteration of the gait pattern in 25 children with Duchenne muscular dystrophy, using body-worn inertial sensors during a long walking distance. Normalized spatiotemporal gait parameters and their variability were extracted from the angular velocity of the shanks; the smoothness of the trunk movement was assessed based on the spectral entropy of the acceleration norm. As compared to healthy children, patients with Duchenne muscular dystrophy showed significantly lower stride velocity and a less smooth trunk movement. When the group of patients was divided into mild and moderate based on the Motor Function Measure, the authors noticed significantly higher values both for cadence and stride velocity, as well as improved trunk smoothness in the mild versus moderate group. The potential of such parameters to distinguish between different disease states opens new perspectives for the objective assessment of efficacy of the new therapies associated with Duchenne muscular dystrophy.

Early mortality in Duchenne muscular dystrophy (DMD) is related to cardiac and respiratory complications. A phase IIa double-blind randomized placebo-controlled clinical trial was conducted to investigate the tolerability and efficacy of idebenone therapy in children with DMD. Twenty-one DMD patients (aged 8-16 years) were randomly assigned to daily treatment with 450 mg idebenone (Catena®) (n=13) or placebo (n=8) for 12 months. All subjects completed the study and idebenone was safe and well tolerated. Idebenone treatment resulted in a trend (p=0.067) to increase peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. A significant respiratory treatment effect on peak expiratory flow was observed (p=0.039 for PEF and p=0.042 for PEF percent predicted). Limitations of this study were the small sample size, and a skewed age distribution between treatment groups. Data from this study provided the basis for the planning of a confirmatory study., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The authors report a pilot open-label two-center therapeutic trial of oxatomide in 14 steroid-naive DMD boys aged 5-10 years. Comparison of linear evolutions between 3 months medication-free lead-in periods and 6 months treatment periods showed no significant differences in quantitative (QMT) and manual (MMT) measurements of muscle strength and timed functional tests. A modest mitigation of strength deterioration over time cannot be excluded.