Physical Therapist test for muscular dystrophy in pediatrics patients

RESEARCH ARTICLE Development of a Functional Assessment Scale for Ambulatory Boys with Duchenne Muscular Dystrophy Elaine Scott 1* , Michelle Eagle 2, Anna Mayhew 2, Jenny Freeman 3, Marion Main 4, Jennie Sheehan 5, Adnan Manzur 6, Francesco Muntoni 6& The North Star Clinical Network for Paediatric Neuromuscular Disease † 1Muscular Dystrophy Campaign, London, UK2Institute of Human Genetics, Newcastle, UK3University of Shefﬁeld, Shefﬁeld, UK4Great Ormond Street Hospital, London, UK5Evelina Children’s Hospital, London, UK6Dubowitz Neuromuscular Centre, Institute of Child Health, UCL, London, UK Abstract Background and Purpose.The aims of this study were to develop a clinical assessment scale to measure functional ability in ambulant boys with Duchenne muscular dystrophy and to determine the reliability of the scale in multiple centres in the UK.Methods.Focus groups and workshops were held with experienced paediatric neuromuscular phy- siotherapists to determine scale content. A manual was prepared with accompanying videos, and training sessions were conducted. A total of 17 physiotherapists from participating centres used the videos to determine inter-rater reliability.

Five determined the intra-rater reliability.Results.Strength of agreement for these groups based on total subject scores was very good (0.95 and≥0.93 for consistency and absolute agreement, respectively). Test–retest ability was high, with perfect agreement between occasions for all but two items of the scale.Conclusions.Our study indicates that the North Star Ambulatory Assessment is practical and reliable. It takes only 10 minutes to perform and incorporates both univer- sally used timed tests as well as levels of activities, which allow assessment of high-functioning boys with Duchenne muscular dystrophy. Copyright © 2011 John Wiley & Sons, Ltd.

Received 27 January 2011; Revised 21 May 2011; Accepted 26 June 2011 Keywords ambulant; assessment; Duchenne muscular dystrophy *Correspondence Elaine Scott, MPhil, MCSP, c/o Muscular Dystrophy Campaign, 61 Southwark Street, London SE1 0HL, UK.

Email: [email protected] †The North Star Clinical Network for Paediatric Neuromuscular Disease: Collaborators (53): Manzur A.Y., Muntoni F., Robb S., Main M., Kemp J.

(Great Ormond Street Hospital, London), Scott E. (Muscular Dystrophy Campaign, London), Bushby K., Straub V., A. Sarkozy, E. Strehle, R.

Venkateswaran, Eagle E., Mayhew A. (Institute of Human Genetics, Newcastle), Roper H., McMurchie H., Grace A. (Heartlands Hospital, Birmingham), Spinty S., Peachey G., Shillington S. (Alder Hey Children’s Hospital, Liverpool), Quinlivan R., Groves L. (Robert Jones and Agnes Hunt Royal Orthopaedic Hospital, Oswestry), Wraige E., Jungbluth H., Sheehan J., Spahr R. (Evalina Children's Hospital, London), Hughes I., Bateman E., Cammiss C. (Royal Manchester Children's Hospital), Childs A.M., Pallant L., Psyden K. (Leeds General Inﬁrmary), Baxter P. (Shefﬁeld Children's Hospital), Naismith K., Keddie A. (King's Cross Hospital, Dundee), Horrocks I., McWilliam R., Di Marco M. (Yorkhill Children's Hospital, Glasgow), Hartley L., Sheen B., Fenton-May J. (University Hospital Wales, Cardiff), Jardine P., Majumdar A., Jenkins L. (Frenchay Hospital, Bristol), Chow G., Miah A. (Queen's Medical Centre University Hospital, Nottingham), de Goede C. (Preston Royal Hospital), Thomas N., Geary M., 101 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. Palmer J (Southampton General Hospital), White C., Greenﬁeld K. (Morriston Hospital, Swansea), MacAuley S. (Royal Belfast Hospital for Sick Children), Baxter A., Yirrell Y., Longman C. (Royal Hospital for Sick Children, Western General Hospital, Edinburgh).

Published online 23 September 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pri.520 Introduction The development of validated outcome measures in Duchenne muscular dystrophy (DMD) has become in- creasingly important because of the need to monitor disease progression and the impact of treatments, such as intermittent or daily steroids (Manzur et al., 2008a), and the requirement for reliable functional out- come measures for use in clinical trials (Manzur et al., 2008b; Mercuri et al., 2008). Since the original work of Brooke et al. (1981) and Scott et al. (1982) in the early 1980s on outcome measures for DMD, numerous papers relating to the use of a large variety of outcome measures for this condition have been published (e.g. McDonald, 2002; Kohler et al., 2005; Scott and Mawson, 2006; Mayhew et al., 2007; Davis et al., 2010; McDonald et al., 2010), and much work has been carried out, or is currently underway, to evaluate the usefulness of these measures in clinical and re- search settings via the TREAT-NMD clinical and research EU-funded network of excellence (www.treat-nmd.eu) and other related programmes. The focus of this study, however, is on the development and validation of a functional scale for needs of the North Star Project in the UK.

The North Star Clinical Network for Paediatric Neu- romuscular Disease Management is a collaboration of 17 specialist neuromuscular centres in the UK whose overall aim is to optimize the management of children with DMD (Scott et al., 2007). The key objective of the net- work was to standardize clinical assessment protocols and pharmacological interventions such as corticosteroid use for ambulant boys with DMD. Clinicians and therapists from the clinical network identiﬁed functional measures as the most clinically relevant outcomes in monitoring disease pro- gression (North Star network internal report), and patients and their relatives relate more to measures of function as opposed merely to muscle strength. There is a need for such functional measures to be valid for the patient group and context in which they are to be used, to provide reliable data, which in the context of the North Star Project means data from mul- tiple centres, to be responsive to change and to be feasible for the patient group and setting.

Many scales have been developed previously to assess the functional abilities of boys with DMD and otherneuromuscular conditions; however, each of these scales had limitations as evaluation instruments for steroid-trea- ted ambulant boys with this condition. These included a lack of sensitivity to change and a lack of data on reliability, practicality and ease of use across multiple clinical centres.

The scales developed speciﬁcallyforDMDbyVignosetal.

(1963) and Brooke et al. (1981) provide simple ordinal- level data, which do not offer the degree of sensitivity re- quired to assess the effect of novel treatments. The Egen Klassiﬁkation (EK) Scale (Steffensen et al., 2001, 2002) and the Motor Function Measure (Bérard et al., 2005, 2006) are both examples of substantial, comprehensively developed measures for the assessment of neuromuscular disorders. However, the EK Scale addresses non-ambulant function only, and the Motor Function Measure is lengthy and neither disease nor stage speciﬁc. The most commonly used functional scale in the UK, the Hammersmith Motor Ability Scale (HMAS) (Scott et al., 1982), is satisfactorily used within a clinical setting; but reliability and validity have never been established. Furthermore, the scale was developed before corticosteroids were widely used and suf- fers from ceiling effects in children beneﬁtting from the positive effect of this medication (personal observation of the authors). The focus of this study is therefore on the ini- tial development of a functional assessment scale for am- bulant children with DMD, the North Star Ambulatory Assessment (NSAA).

There were two aims of this study:

to describe the initial development of the scale as a clinical assessment tool to present the initial training and reliability data from the North Star group of physiotherapists. Methods Development of the North Star Ambulatory Assessment Year 1—construction and development The intent was to develop a clinical scale to evaluate change in the physical abilities of ambulatory boys with DMD. This included boys across a range of ability levels Development of a Scale for Duchenne MDE. Scottet al.

102 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. from those only just able to walk to those with higher functional abilities such as running and jumping. As there are 17 centres involved in the North Star clinical network, it was important that minimal equipment should be re- quired for standardization of use across sites. Given the behavioural difﬁculties that are common in young boys with DMD and the limited time available in clinic settings, it was also important that the time to complete the scale should be kept to a minimum.

Although the HMAS has the limitations stated pre- viously, it has an acknowledged clinical utility and a long history of use in the UK. It was therefore used as a basic framework from which the NSAA was devel- oped. A focus group of specialist neuromuscular phy- siotherapists (M. M., M. E. and J. S., with E. S.) was convened to determine the structure and content of the scale. Domain of content (Portney and Watkins, 2000) for the NSAA was deﬁned as the gross motor ability in ambulant DMD children. The underpinning theoretical construct is that these boys lose functional ambulation in a recognizable pattern due to the pri- mary underlying pathology of progressive muscle deterioration and related complications such as con- tractures. Activities included were those necessary to remain functionally ambulant including the ability to rise from theﬂoor and getting from sitting to stand- ing. Head raise and standing on heels were included as these are difﬁcult even in the early stages of thedisease while children are still ambulant and were seen as clinically relevant. Other activities such as hopping, jumping and running are unusual in non-steroid- treated children yet are frequently seen in children treated with steroids, whether on intermittent or daily regimes. An example of items included in the NSAA is given in Table 1.

The scores for each item are described in terms of clinically signiﬁcant changes in the functional abilities seen in this patient group, reﬂecting the pattern of dis- ease progression. Sensitivity to change has thus been addressed theoretically with the description of the item categories in terms of‘clinically signiﬁcant change’ (Bain and Dollaghan, 1991), that is, change that denotes a true change in a patient’s abilities not merely due to natural variability of performance, or matura- tion. Following a series of four focus group meetings, a manual to enable standardized use of the scale was developed and introduced at a series of eight work- shops for experienced neuromuscular physiotherapists in the North Star network. After a six-month period of clinical use and assessment, the scale was formally reviewed, and amendments were made to the descrip- tion of the activities to make it easier to grade each task; however, no new items were included, and none were removed. In this manner, face and content validity were addressed by the initial focus group then further validated by the wider expert group of the North Star Table 1.North Star Ambulatory Assessment, example of test items Test item 1: Stand Starting positionFeet should be no further than 10cm apart and heels on the ground if possible. Arms by sides. NO shoes should be worn.

InstructionCan you stand up tall for me for as long as you can and as still as you can for three seconds with your heelsﬂat on the ground?

Scoring detailWhen counting to 3–Use“And 1 - and 2 - and 3”so that three seconds is achieved on the word of 3.

Best done on theﬂoor rather than on a mat. Whichever is chosen maintain consistency through repeated testing sessions.

Score 2 - Minimum count of 3 seconds.

Score 2Stands upright, still, symmetrical, without compensation (heelsﬂat legs in neutral) for minimum count of 3 seconds 1Stands still but with compensation (e.g. on toes or with legs abducted or with bottom stuck out) for minimum count of 3 seconds 0Cannot stand still or independently, needs support (even minimal) Test item 14: Jump Starting positionStanding on theﬂoor, feet fairly close together. No shoes should be worn.

InstructionHow high can you jump?

Scoring detailWant height, not forward movement. Small amount of forward movement acceptable Score 2Both feet at the same time, clear the ground simultaneously 1One foot after the other (skip) or does not fully clear both feet at the same time.

0Unable E. Scottet al.Development of a Scale for Duchenne MD 103 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. clinical network. Figure 1 summarizes the process of development and review of the measure.

Year 2—reliability testing and ongoing training Initial training in the use of the scale included work- shops, centre visits by the project coordinator, where joint patient assessments were undertaken, and a period where assessors piloted the scale in clinical practice.

Two sets of reliability data are presented:

six subjects evaluated byﬁve of the North Star group of therapists three subjects evaluated by 17 therapists from all par- ticipating centres.

Table 2 provides an outline as to which raters evalu- ated which subjects for these data sets. Video was taken of boys with a range of differing abilities, and each eval- uator was asked to independently score each child.Scoring was carried out in conﬁdence during group sessions, with the coordinator present. Video of scale items could be viewed more than once on request.

Score sheets were submitted to the coordinator.

Further, to this intra-rater reliability was examined with ﬁve experienced physiotherapists who independently scored the same individual from video on two occasions, with a one-month interval between evaluations.

The scale has subsequently been adopted as a stan- dard clinical assessment tool for use in over 17 paediat- ric neuromuscular centres in the UK.

Statistical analysis Inter-rater reliability was assessed according to the methods outlined in the study by Streiner and Norman (2003). The intraclass correlation coefﬁcient (ICC) for consistency among raters and the ICC for absolute agreement were computed. The ICC for consistency assesses whether raters were consistent in the order in which they placed individuals, that is, were boys rated in the same order for functional ability by all raters from worst to best (irrespective of the actual value).

The ICC for absolute agreement assesses whether raters agreed with each other with respect to the actual values they assigned individuals. Given the mathematical equivalence between the ICC and the kappa statistic (Fleiss and Cohen, 1973), interpretation of the tabu- lated ICC values was based on the semantic categories adapted by Altman (1991) from Landis and Koch, as shown in Table 3. However, the kappa statistic provides a poor summary measure of agreement when prevalence is low, as it was for some of the features investigated here.

As a result, the percentage classiﬁed into each category across all raters and all children (n= 30 for the smaller group ofﬁve therapists, andn=51 for the group of 17 therapists) has also been tabulated for each variable.

Intra-rater reliability was assessed using data fromﬁve assessors who each assess the same, single individual on two occasions. As agreement was perfect for all but two Figure 1Summary of the North Star Ambulatory Assessment de- velopment process Table 2.Outline of rater to subject evaluations SubjectRaters 1234567891011121314151617 A xxxxxxxxxxxxxxxxx B xxxxxxxxxxxxxxxxx C xxxxxxxxxxxxxxxxx D xxxxx E xxxxx F xxxxx Table 3.Interpretation of kappa statistic and intraclass correlation coefﬁcient Value of K Strength of agreement <0.20 Poor 0.21–0.40 Fair 0.41–0.60 Moderate 0.61–0.80 Good 0.81–1.00 Very good Development of a Scale for Duchenne MDE. Scottet al. 104 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. of the items on the scale, it was not possible to calculate the test–retest coefﬁcient, and thus, only the percentage agree- ment has been presented.

Results Year 1—construction and development of the scale Following a substantial periodof development and special- ist review, a 17-item scale was agreed. Aspects of theoreti- cal construct and content validity were addressed, as was thefeasibilityofuseinmultipleclinicalcentresforthispa- tient group. A document standardizing the test method was compiled and circulated to all involved in the clinical network, and workshops and site visits were undertaken to ensure standardized application of the scale (full test details are available from www.muscular-dystrophy.org/ how_we_help_you/for_professionals/clinical_databases).

Year 2 Five physiotherapists evaluated the videos of six boys by using the NSAA scale. Strength of agreement for this group (Table 4) based on total subject scores was very good (0.95 for both consistency and absolute agree- ment). Fifteen of the 17 individual items were ratedgood or very good for consistency, and 15 for absolute agreement. The 17 physiotherapists involved in data collection for the network evaluated the videos of three boys. All 17 evaluated all videos. As with the previous data for theﬁve physiotherapists and six boys, the strength of agreement (Table 5) when based on total subject scores was very good (0.95 and 0.93 for consis- tency and absolute agreement, respectively). Nine of the individual items were rated good or very good for consistency, and nine for absolute agreement. Where items have been rated poor or fair on ICC analysis, for example, rise fromﬂoor, there was an overall good agreement among therapists by the percentage classi- ﬁed into category 1, that is, over 90% of the therapists classiﬁed the subjects as scoring 1 (signs of Gowers’ manoeuvre). This, however, meant that there was a low prevalence across the range of scores—none of the subjects in this study were scored as unable to rise from theﬂoor (Tables 4 and 5). This issue of preva- lence across the range of scores (2,1,0) and its effect upon results will be returned to in the Discussion and Conclusion sections.

Although the numbers were small (onlyﬁve phy- siotherapists), the agreement between occasion 1 and occasion 2 was perfect for all but two of the items, jump and run (Table 6).

Table 4.Inter-rater reliability: percentage classiﬁed into each category, together with intraclass correlation coefﬁcients (ICCs),n=30 (six subjects,ﬁve assessors) Test item% classiﬁed as: ICC:

0 1 2 Consistency Absolute agreement Stand 3.3 46.7 50.0 0.91 0.90 Walk 53.3 46.7 0.89 0.87 Sit to stand 50.0 50.0 0.78 0.75 Single leg stand (right) 50.0 50.0 1.00 1.00 Single leg stand (left) 33.3 66.7 0.75 0.72 Climb step (right) 16.7 83.3 1.00 1.00 Climb step (left) 20.0 80.0 0.82 0.80 Descend step (right) 23.3 76.7 0.76 0.73 Descend step (left) 40.0 40.0 0.68 0.64 Lying to sitting 1 55.2 44.8 0.41 0.38 Rise fromﬂoor 96.7 3.3 0.00 0.00 Lift head 66.7 23.3 76.7 0.76 0.73 Stand on heels 10.0 16.7 16.7 0.85 0.83 Jump 30.0 26.7 63.3 0.78 0.75 Hop (right) 36.7 30.0 40.0 0.76 0.73 Hop (left) 23.3 40.0 23.3 0.78 0.75 Run 26.7 50.0 0.74 0.71 Total score0.95 0.95 1One observation missing. E. Scottet al.Development of a Scale for Duchenne MD 105 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. Discussion The NSAA has been developed by expert paediatric neuromuscular physiotherapists speciﬁcally for use in ambulant children with DMD, thus ensuring that the content of the scale is clinically meaningful and appro- priate. Experience from clinical use has shown that the NSAA takes approximately 10 minutes to complete,including timed tests, and its ease of administration means that it can be used both in specialist clinics and community settings. Evaluation of the feasibility of its administration by the North Star therapists indicates that compliance is good even in children with learning or behavioural problems, a feature that characterizes one-third of all DMD boys (Emery and Muntoni, 2003).

Lead physiotherapists from all 17 centres involved in data collection for the project participated in the reli- ability exercise, where the main focus was on ensuring standardized scoring and rater agreement. Strength of agreement when based on total subject scores was found to be excellent. This varied substantially, how- ever, when individual test items were considered, par- ticularly for the larger therapist group. Although good to very good agreement on analysis by ICC was gained for many test items on the NSAA, very poor results were gained for six by the larger therapist group. This apparently poor strength of agreement is confounded when the percentage classiﬁed into each category is considered. The percentage classiﬁed results show that there was actually excellent agreement among thera- pists for most of these test items, but the majority of subjects were considered to fall into one category (see item 11 (rise fromﬂoor) in Tables 3 and 4). The kappa statistic, and therefore the ICC, provides a poor sum- mary measure of agreement when prevalence of Table 5.Inter-rater reliability: percentage classiﬁed into each category, together with intraclass correlation coefﬁcients (ICCs),n=51 (three subjects, 17 assessors) Test item% classiﬁed as: ICC:

0 1 2 Consistency Absolute agreement Stand 3.9 60.8 35.3 0.87 0.83 Walk 66.7 33.3 0.88 0.84 Sit to stand 41.2 58.8 0.83 0.78 Single leg stand(right) 68.6 31.4 0.94 0.92 Single leg stand (left) 64.7 35.3 0.94 0.92 Climb step (right) 2.0 98.0 0.00 0.00 Climb step (left) 13.7 86.3 0.38 0.31 Descend step (right) 19.6 80.4 0.28 0.22 Descend step (left) 19.6 80.4 0.30 0.24 Lying to sitting 64.7 35.3 0.70 0.64 Rise fromﬂoor 90.2 9.8 0.10 0.08 Lift head 7.8 92.2 0.05 0.04 Stand on heels 66.7 23.5 9.8 0.81 0.77 Jump 21.6 25.5 52.9 0.60 0.53 Hop (right) 29.4 41.2 29.4 0.78 0.73 Hop (left) 39.2 47.1 13.7 0.74 0.68 Run 37.2 21.6 41.2 0.54 0.47 Total score0.95 0.93 Table 6.Agreement between occasion 1 and occasion 2 (n=5) Test item Agreement (%) Stand 100 Walk 100 Sit to stand 100 Single leg stand (right) 100 Single leg stand (left) 100 Climb step (right) 100 Climb step (left) 100 Descend step (right) 100 Descend step (left) 100 Lying to sitting 100 Rise fromﬂoor 100 Lift head 100 Stand on heels 100 Jump 80 Hop (right) 100 Hop (left) 100 Run 60 Development of a Scale for Duchenne MDE. Scottet al.

106 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. different categories is low, as it was for some of the fea- tures investigated here, and so it should be interpreted with caution. Although the three subjects presented with varying abilities, all achieved an average total score of 18 or over. The evaluation of a bigger group of sub- jects with a wider variety of abilities would have addressed these issues; however, even this may not alle- viate this issue where prevalence in any one category is low (Fleiss and Cohen, 1973).

A subsequent study in Italy by Mazzone et al. (2009) reported theirﬁndings regarding training needs and re- liability studies for the NSAA for a substantially larger group of patients. Their initial results, following the ﬁrst phase of training, were poor (ICC<0.05), but fol- lowing a second phase, the ICC for all items was≥0.75, with all but one item indicating a very good level of agreement. Two of the items (lift head and run), which proved problematic to gain agreement in theﬁrst phase of the Italian study, were also the same for the larger North Star group (Table 4). However, without the per- centage classiﬁed data, it is not possible to know if these poor ICC results are an artefact of the low prevalence across categories or of a lack of clarity with the wording of the scale. Neither of these items were a cause for concern with the smaller North Star group or the Ital- ian group following their second phase of training. The issue of training and in particular consensus building, as demonstrated in Mazzone’s paper, is an important one for any clinician-rated assessment scale, such as the NSAA. The medium that is used to translate the patient’s performance of an activity to a point on the scale is observation on the part of the assessor. The assessor’s interpretation/understanding of the wording of the scale therefore becomes an important factor in avoiding measurement error and achieving reliable results from the scale. Translation into another lan- guage may also play a factor in the interpretation of the scale and needs careful consideration in interna- tional studies. Ongoing training for the North Star clin- ical network includes an annual reliability review to ensure consistency and quality of data collated for the national database. The Italian study reported excellent inter-rater reliability (ICC = 0.995) based on total scores comparable with the initial reliability studies from the North Star group. They also reported a very high level of intra-rater reliability (0.95) in their com- prehensive work.

Although the initial phase of both the UK and the Italian studies indicated potential issues withreliability indices for a small number of the scale items, the decision was made, because of expert clini- cal opinion as to their clinical importance for this pa- tient group, to continue to include these items.

Further, rigorous evaluation of the psychometric properties of the scale in a large population of boys with DMD is currently underway using Rasch meth- odology. Following this, recommendations may be made for scale modiﬁcations, balancing high levels of validity and reliability with the need for clinical and statistical relevance.

The scale has now been in use for more than four years, and data from over 300 DMD boys are being col- lated, with the formal consent of families and assent of patients, on the North Star database in the UK. The da- tabase holds comprehensive national data on clinical performance and outcomes from patients who attend participating centres. Consistent and standardized lon- gitudinal clinical data, of which the NSAA is part, are therefore being collated on a cohort of children with DMD offering a valuable tool for clinical audit and re- search purposes.

The North Star clinical scale is now also been used to document clinical response in experimental clinical trials (Cirak et al., 2009; Kinali et al., 2009). The new challenge, which is being considered, is how to expand the scale to include non-ambulant children and young adults, as natural history data in this group of indivi- duals are scant. Conclusion The NSAA is a reliable, robust, practical test that can be realistically used across a range of settings with mini- mal, universally available equipment and completed in a short timeframe. The initial results of the reliability analyses for the North Star group of physiotherapy assessors show an excellent level of agreement, which is further demonstrated in the Italian study (Mazzone et al., 2009). The scale incorporates the important dis- ease milestones such as rising from theﬂoor and walk- ing ability as well as incorporating new skills that are acquired by DMD boys treated with steroids. A study is currently underway to further evaluate the theoreti- cal content and construct validity, reliability and sensi- tivity to change of the scale by using the Rasch methodology. The authors also plan to present the lon- gitudinal data from the North Star database in due course. E. Scottet al.Development of a Scale for Duchenne MD 107 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. Acknowledgements The North Star Project is supported and funded by the Muscular Dystrophy Campaign. The MRC Neuromus- cular Centre’s support to the North Star Database and the Muscular Dystrophy Campaign Centre’s grant to the Dubowitz Neuromuscular Centre are also gratefully acknowledged. Professor Muntoni is supported by the Great Ormond Street Hospital Children’s Charity.

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