Physical Therapist test for muscular dystrophy in pediatrics patients

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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Scottet al.Development of a Scale for Duchenne MD 109 Physiother. Res. Int.17(2012) 101–109 © 2011 John Wiley & Sons, Ltd. Copyright of Physiotherapy Research International is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder’s express written permission. However, users may print, download, or email articles for individual use.
Physical Therapist test for muscular dystrophy in pediatrics patients
1 Curso de Fisioterapia, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, SP, Brasil2 Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor, FMRP, USP, Ribeirão Preto, SP, Brasil3 Departamento de Neurociências e Ciências do Comportamento, FMRP, USP, Ribeirão Preto, SP, BrasilReceived: 08/11/2013 Revised: 12/18/2013 Accepted: 02/17/2014 original article Balance and muscle power of children with Charcot-Marie-Tooth Tais R. Silva¹, Amanda Testa¹, Cyntia R. J. A. Baptista², Wilson Marques Jr 3, Ana C. Mattiello-Sverzut² ABSTRACT | Background: In certain diseases, functional constraints establish a greater relation ship with muscle power than muscle strength. However, in hereditary peripheral polyneuropathies, no such relationship was found in the literature. Objective: In children with Charcot-Marie-Tooth (CMT), to identify the impact of muscle strength and range of movement on the static/dynamic balance and standing long jump based on quantitati ve and functional variables. Method : The study analyzed 19 participants aged between 6 and 16 years, of both genders and with clini cal diagnoses of CMT of different subtypes. Anthropometric data, muscle strength of the lower limbs (hand-held dynamometer), ankle and knee range of movement, balance (Pediatric Balance Scale) and standing long jump distan ce were obtained by standardized procedures. For the statistical analysis, Pearson and Spearman correlation coeffici ents were used. Results: There was a strong positive correlation between balance and the muscle strength of the right plant ar flexors (r=0.61) and dorsiflexors (r=0.59) and a moderate correlation between balance and the muscle str ength of inversion (r=0.41) and eversion of the right foot (r=0.44). For the long jump and range of movement, there was a weak positive correlation with right and left plantar flexion (r=0.20 and r=0.12, respectively) and left popliteal angle (r=0.25), and a poor negative correlation with left dorsiflexion (r=–0.15). Conclusions: The data on the patients analyzed suggests that the maintenance of dista l muscle strength favors performance during balance tasks, while limitations in the range of movement of the legs seem not to be enough to influence the performance of the horizontal long j ump. Keywords: Charcot-Marie-Tooth disease; strength; balance; range of movement; assessment; physical therapy. HOW TO CITE THIS ARTICLE Silva TR, Testa A, Baptista CRJA, Marques Jr W, Mattiello-Sverzut AC. Balance and muscle power of children with Charcot- Marie-Tooth. Braz J Phys Ther. 2014 July-Aug; 18(4):334-342. http://dx.doi.org/10.1590/bjpt-rbf.2014.0055 Introduction Charcot-Marie-Tooth disease (CMT) is a hereditary polyneuropathy with various subtypes. The common clinical phenotype is the impairment of motor and sensory peripheral nerves due to a demyelinating and axonal degenerative process¹. The predominant distal muscle weakness may cause significant motor dysfunction in ambulation, participation in daily life, socio-cultural activities in both children and adults. It is important to note that weakness of the ankle dorsiflexors occurs in association with shortening of the plantar flexor muscles and the development of foot deformities 2. The main clinical hypothesis for the development of foot deformities focuses on the intimate relationship between the imbalance in the strength of the invertor and evertor muscles of the feet and overload of the plantar flexor muscles, in contrast to the weakness of the dorsiflexor group 3. The latter is considered the main manifestation of the disease and contributes to foot deformity (e.g. pes cavus), ankle contracture, poor motor function and difficulty in walking in affected children and adults 2. It is believed that losses in the range of motion (ROM) of distal muscles in patients with CMT compromise muscle power as they impair the stretching-shortening cycle. In the case of the horizontal jump (i.e.standing long jump), 50% of the muscle performance is attributed to the ankle 4. Thus, the ROM in the lower limbs can be correlated with the performance in a standing long jump test used to infer muscle strength. Muscle strength, ROM, and different neuromuscular demands in the lower extremity are factors that modify the limits of postural stability and may influence the performance of a specific functional task 5. Therefore, the selection of physical  334 Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 http://dx.doi.org/10.1590/bjpt-rbf.2014.0055 CMT disease: balance and muscle power therapy procedures in CMT disease can be targeted and assertive if based on the understanding of the actual contributions of the variables involved in static and dynamic balance. It is important to study CMT hereditary polyneuropathy because its incidence is relatively high, affecting 1 in every 2,500 individuals 2. Although the initial symptoms of the disease usually appear in the first or second decade of life with slow progression over the subsequent decades, adults are the target population in the majority of studies 6-8. Interventional studies involving drugs are still in progress because there is no effective therapy for CMT disease 1, and the use of orthoses presents controversial results 8. In addition, studies that focused on clarifying the contribution of the major deficits (i.e. musculoskeletal, neuromuscular, and biomechanical) to balance in children with CMT are limited. Thus, it becomes relevant to investigate the behavior of the biomechanical variables during the initial phase of the disease. This is a preliminary step to the proposal of physical therapy interventions that can potentially help in the rehabilitation of these children and adolescents. In children and adults, the triad of muscle weakness, joint hyper/hypomobility, and compensatory biomechanical disorders can cause significant motor dysfunctions of distal-proximal predominance with loss of balance, ambulation, and hampered participation in activities of daily living 2. Similarly, the relationship between passive ROM with horizontal jump, measured using the standing long jump test, and balance, assessed with the Pediatric Balance Scale (PBS), were tested. Briefly, the aim of this study was to evaluate the influence of passive ROM and strength of the major muscle groups of the lower limbs on the static/dynamic balance and horizontal jump capacity of children with CMT disease. Method This study included a total of 19 child and adolescent participants who were admitted to the Neurogenetic Disorders Outpatient Clinic of the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP/USP), Ribeirão Preto, São Paulo state, Brazil, between 2011 and 2012 with a confirmed CMT diagnoses. The participants were of both genders, aged between 5 and 16 years, were able to walk independently, and had no diseases associated with CMT disease that affect the cardiorespiratory system. Consent was obtained from the parents or guardians who filled out the informed consent form previously approved by the Research Ethics Committees of the HCFMRP/USP (Number 4334/2011). In a standardized manner, anthropometric data, goniometry, muscle strength (hand-held dynamometer – Lafayette Instrument Co., Lafayette, UK), lower limb power (long jump test), and static/ dynamic balance (Pediatric Balance Scale) were obtained from all participants. The passive ROM was measured for the knees (popliteal angle) and ankles (plantar flexion and dorsiflexion), according to the method described by Marques 9. The measurements were performed using a universal goniometer (CARCI – Indústria e Comércio de Aparelhos Cirúrgico e Ortopédicos Ltda.). The muscle strength (in kilogram-force) of the hip extensors, knee extensors, and dorsiflexors, plantar flexors, supinators, and pronators of the foot were measured three times using a hand-held dynamometer, alternating between the right and left lower limbs to prevent fatigue. The highest value was used for analysis. To ensure that the dynamometer was kept perpendicular to the segment being tested and as distal as possible, an assistant stabilized the participant during the measurements, and the following bodily positions were adopted: supine, lower limbs in the anatomical position and feet out of the stretcher to measure the muscle strengths of the dorsiflexors, plantar flexors, supinators and pronators; the prone position with knee flexed to 90° to measure the muscle strength of the hip extensors; and the sitting position with knee flexed to 90° to measure the muscle strength of the knee extensors. The voice command “force” was used during the tests while the evaluator prevented any range of motion to ensure an isometric contraction for five seconds. The standing long jump test, also called the horizontal jump or broad jump, is easy to apply and requires only chalk or pencil to mark the ground and a plastic tape measure or self-retracting tape measure to measure the distance jumped. The participants were positioned behind a line marked on the ground with the feet slightly apart and were asked to jump the greatest horizontal distance possible by bending the legs and using the impulse generated by swinging the arms 10. This strategy allowed balance to be restored or maintained through the transfer of angular momentum from the arms to the rest of the body. Three attempts were made, and the highest value was used for analysis. The result was given in centimeters, measuring the distance between the 335   Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 Silva TR, Testa A, Baptista CRJA, Marques Jr W, Mattiello-Sverzut AC starting line and the mark achieved by the calcaneus on the ground. The PBS was used to measure functional balance because it was suitable for school-aged children with mild to moderate motor disability, according to Franjoine et al. 11. The test lasted approximately 15 minutes and did not require the use of specialized equipment, and it provided clinical data for the measurement of functional balance tasks. The brazilian version of the PBS described by Ries et al. 12 was used to apply the test. The following materials were used: a chair with back support, adjustable height, and arm rests; markers for the feet; stopwatch; tape measure; and step stool. The participants were instructed, through demonstrations, how they were to perform the tests. A preliminary trial of each proposed task was allowed for each tested item. The PBS consisted of 14 items that required the child to perform static and dynamic balance tasks. Each item was be scored from 0 to 4, with 4 corresponding to a better ability to perform the required task. The scores on each of the 14 tasks were summed, and the final score was determined from this number, with a maximum value of 56. Higher scores were associated with greater ability to perform the required task and therefore with better balance. In healthy children from the age of seven, the maximum score of 56 should normally be achieved, and there is no mention in the literature regarding the classification of lower scores 11. To meet the study objective, which was to correlate the dynamometry data of lower limbs with balance and range of motion data of the lower limbs with the horizontal impulse measured by the standing long jump test, the Pearson correlation coefficient ( r) and the Spearman correlation coefficient, which quantify the association between two quantitative variables, were used. These coefficients ranged from –1 and 1. A value 0 of (zero) indicated that there was no linear correlation; 1 indicated perfect linear correlation; and –1 also indicated a perfect negative linear correlation (i.e., when one of the variables increased, the other decreased). Values closer to 1 or –1 indicated stronger linear correlation between the two variables. The classification of the Spearman correlation coefficients was performed based on the study by Hulley et al. 13, and the classification of the Pearson correlation coefficients was performed based on the study by Pagano and Gauvreau 14. The following correlations were tested: muscle strength × balance and, standing long jump × ROM. Results The anthropometric data and the classification of the participants are shown in Table 1. Among the 19 patients in the study, nine were males and ten were females; the mean age was 10.11 years (standard deviation: 2.64), mean weight was 40.59 kg (standard deviation: 15.37), and mean height was 1.43 m (standard deviation: 0.18). Considering the normative values provided by the World Health Organization (WHO) 15, nine participants had a body mass index (BMI) appropriate for their age, while four participants were underweight, two were overweight, and four were obese. The lower limb muscle strength, passive ROM, standing long jump test, and PBS scores obtained are shown in Table 2. The isometric muscle strength values were not proportional to the age of the participants. The dorsiflexor, invertor, and evertor muscle groups presented the lowest isometric muscle strength values, with the dorsiflexion strength being zero in participants C and K. For balance, which was determined using the PBS, high scores were observed for the participants with CMT (scores ranged between 51 and 56), indicating a good overall performance. However, considering the PBS items separately, the most challenging tasks were identified as follows: standing with eyes closed, standing with one foot in front, standing on one foot, retrieving an object from the ground, and reaching forward. The ROM data indicated that bilateral ankle joint mobility was preserved except in three cases in which there was limitation (participants H, N, and R), with dorsiflexion being less than 10 degrees, and in three cases with lack of mobility (participants K, M, and O), with dorsiflexion being equal to or less than zero. The bilateral popliteal angle was preserved in most participants (except for values lower than 140°) (Table 2). For the standing long jump test, there was no increase in performance with age, and the values from 7 (A, H, I, K, L, O, Q) of the 19 participants were lower than the values described as normative 16 (Table 2). Correlations between PBS and lower limb muscle strength The results of the Spearman test indicated a strong positive correlation between balance and the strength of the following muscle groups: right plantar flexors (r=0.61; p=0.01), right dorsiflexors (r=0.59; p=0.01),  336 Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 CMT disease: balance and muscle power and left dorsiflexors (r=0.59; p=0.01) and a moderate correlation between balance and the strength of the following muscle groups: right invertors (r=0.44; p=0.06), left invertors (r=0.41; p=0.08), and right evertors (r=0.44; p=0.06) – Table 3. Correlations between the standing long jump test and passive ROM of the lower limbs The values obtained in the correlation of the standing long jump test with the ROM of the lower limbs showed a weak positive correlation between the ROM of right plantar flexion (r=0.20; p=0.41), left plantar flexion (r=0.12; p=0.61), and left popliteal angle (r=0.25; p=0.31). There was a weak negative correlation for left dorsiflexion (r=–0.15; p=0.54), and no correlation was found for right dorsiflexion (r=0.09; p=0.69) or right popliteal angle (r=0.00; p=1.00), as shown in Table 4. Therefore, the data indicated no correlation between ankle and knee joint ROM with muscle strength as demonstrated in the standing long jump test. Discussion This study demonstrated that participants with CMT presented weakness in the following muscle groups: foot evertors, invertors, dorsiflexors and plantar flexors. With the exception of dorsiflexion, the ROMs were preserved. Overall, balance was preserved; however, there was a deficit in specific items of the PBS. The standing long jump test indicated that muscle strength was preserved in the majority of the participants, with certain exceptions. Although, by definition, the sensorimotor impairment in CMT disease is symmetrical, variations in muscle strength, flexibility, and motor coordination have been observed. Thus, some correlations were found only for the strength and ROM of either the right or left side. These correlations suggest that the preserved strength of dorsiflexors and plantar flexors positively influenced performance in tasks that required balance. The ROMs obtained did not seem to have affected the muscle strength. Table 1. Anthropometric data and classification of participants according to th e type of CMT. Age (years) Participant Gender Weight (Kg) Height (m) BMI Type of CMT 6 A F 36.1 1.3 20*** CMT 1A 6 B F 20.2 1.2 14.5 CMT 1A 6 C F 25.1 1.2 17.7*** CMT**** 8 D M 21.2 1.2 15.0* CMT 1A 9 E M 32.8 1.3 18.5 CMT 1A 9 F F 30.9 1.3 17.2 CMT**** 9 G M 27.7 1.4 14.8* CMT**** 10 H F 51.0 1.4 24.9*** CMT**** 10 I F 28.0 1.4 14.0* CMT**** 10 J F 48.0 1.5 21.3** CMT**** 10 K F 68.0 1.5 28.7*** CMT**** 10 L M 32.5 1.4 15.6* CMT**** 11 M F 53.0 1.7 19.5 CMT**** 11 N M 30.1 1.3 17.5 CMT**** 12 O M 64.0 1.7 21.4** CMT**** 12 P M 50.3 1.6 20.9 CMT**** 13 Q M 37.3 1.4 19.0 CMT**** 14 R F 46.4 1.6 19.1 CMT**** 16 S M 68.7 1.8 20.5 CMT**** * BMI – underweight; ** BMI – overweight; *** BMI – obesity; **** CMT subtype unspecified. 337   Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 Silva TR, Testa A, Baptista CRJA, Marques Jr W, Mattiello-Sverzut AC Table 2. Lower limb muscle strength, goniometry, long jump, and Pediatric Balance Scale (PBS) scores. Participant Age (years) Muscle Strength (Kgf) Goniometry (degrees) Long Jump (cm) PBS IR IL ER EL FPR FPL DFR DFL EKR EKL EHR EHL PFR PFL DR DL PA R PA L A 6 6 5 7 6 17 20 6 5 12 8 13 13 50 42 10 12 190 145 38 55 B 6 4 4 7 6 14 14 7 6 9 10 13 10 65 60 20 20 145 155 60 54 C 6 2 3 2 2 6 8 0 0 14 10 10 12 45 45 10 10 150 140 49 51 D 8 4 6 5 4 18 20 8 5 12 10 14 11 40 45 22 20 140 150 102 55 E 9 6 7 6 7 9 10 9 7 16 17 13 11 50 40 10 0 154 150 115 55 F 9 7 3 4 5 7 10 2 1 17 18 19 17 50 50 10 10 150 150 99 54 G 9 4 5 7 5 21 18 11 9 14 14 16 17 50 45 20 20 155 140 113 56 H 10 8 9 7 10 18 18 7 6 10 10 9 11 32 36 8 10 134 132 59 56 I 10 11 9 7 8 13 15 10 8 24 22 14 13 35 40 22 22 130 140 18 53 J 10 12 12 13 11 19 22 12 12 20 20 16 18 34 34 20 18 145 140 94 56 K 10 4 5 2 2 12 14 0 0 18 19 16 15 50 52 -10 0 140 130 62 51 L 10 6 4 8 10 9 15 6 5 9 9 17 14 40 35 10 17 130 130 63 53 M 11 9 9 10 12 11 9 10 10 20 23 20 24 42 52 0 0 138 138 94 56 N 11 7 5 5 5 15 15 6 4 18 16 13 13 50 40 5 10 140 145 108 56 O 12 7 8 6 6 13 16 7 7 18 17 11 11 36 30 0 0 136 140 83 56 P 12 8 6 7 7 20 20 13 11 15 16 11 11 40 50 20 10 120 120 107 56 Q 13 5 4 5 6 18 10 3 2 11 10 10 10 40 50 10 10 150 136 60 56 R 14 9 12 3 5 24 20 2 2 25 19 14 12 50 40 5 10 128 142 88 55 S 16 12 12 8 9 22 22 26 20 29 28 29 29 50 50 15 12 155 150 180 56 IR= Inverter Right Foot, IL= Inverter Left Foot, ER= Evertor Right Foot, EL= Evertor Left Foot; FPR= Plantar flexor Right; FPE= Plantar flexor Left, DFR= Dorsiflexor Right; DFL= Dorsiflexor Left; EKR= Extensor Knee Right; EKL= Extensor Knee Left; EHR= Extensor Hip Right; EHL= Extensor Hip Left; PFR= Plantar Flexion Right; PFL= Plantar Flexion Left, DR= Dorsiflexion Right, DL= Dorsiflexion Left, PAR= Popliteal Angle Right, PAL= Popliteal Angle Left; 1 st= First Trial; 2 nd= Second Trial, 3 rd= Third Trial; PBS= Pediatric Balance Scale.  338 Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 CMT disease: balance and muscle power Muscle strength and balance Balance is an essential factor in the coordination of motor responses, movements, and postural adjustments. For balance to be effective, several factors, such as the vestibular system, proprioceptive information, visual perception, muscle strength, and joint flexibility need to operate efficiently and harmoniously in the body 17. The muscles surrounding the ankle are essential to maintaining balance because they provide proprioceptive information and correct small postural oscillations, in addition to correcting possible destabilization through muscular torque, thereby regulating the center of gravity and keeping the center of mass located between the feet 18. Typically, the natural history of various subtypes of CMT involves, among other manifestations, the progressive reduction of distal muscle strength, which can impair the maintenance of the center of mass over the base of support, both dynamically and statically 2. The ankle strategy is the most frequently used strategy to maintain balance, and it requires the preservation of the plantar flexor, dorsiflexor, evertor, and invertor muscle strength 19. This strategy is more effective when perturbations to balance are slow and small and the supporting surface is firm (i.e., during static balance) 19. The ankle dorsiflexion produced during the ankle strategy is crucial to maintaining balance after a destabilization because when the forefoot is lifted, a counter-movement force is created, which helps to re-balance the body 20. Thus, the reduction in dorsiflexor muscle strength observed in the participants may explain the deficit found in the maintenance of static balance. In the study, the participants presented data consistent with the data reported in the literature 2,3,5 , Table 4. Pearson coefficient of correlation (r) for passive range of motion of the lower limbs and the long jump test. Measured range of motion of lower limbs Pearson correlation coefficient (r) with the long jump test P value Right Plantar Flexion 0.20 0.41 Left Plantar Flexion 0.12 0.61 Right Dorsiflexion 0.09 0.69 Left Dorsiflexion –0.15 0.54 Right Popliteal Angle 0.00 1.00 Left Popliteal Angle 0.25 0.31 Table 3. Spearman coefficient of correlation (rho) and p value for muscle strength in the lower limbs and the Pediatric Balance Scale (PBS). Muscle Groups Spearman correlation coefficient with balance (rho) P value Right Foot Invertor 0.44 0.06 Left Foot Invertor 0.41 0.08 Right Foot Evertor 0.44 0.06 Left Foot Evertor 0.38 0.10 Right Plantar Flexor 0.61 0.01 Left Plantar Flexor 0.38 0.11 Right Dorsiflexor 0.59 0.01 Left Dorsiflexor 0.59 0.01 Right Knee Extensor 0.15 0.54 Left Knee Extensor 0.20 0.41 Right Hip Extensor –0.07 0.77 Left Hip Extensor 0.04 0.88 339   Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 Silva TR, Testa A, Baptista CRJA, Marques Jr W, Mattiello-Sverzut AC such as reduced muscle strength, especially in the evertor and dorsiflexor muscles and shortening of the plantar flexor muscles. A study conducted by Nyström et al. 21 established reference values for lower limb isometric muscle strength according to the age and body weight of healthy participants. Thus, the data obtained in the current study were compared with the reference values obtained by Nyström et al. 21 using the weight and height of the participants because the reference values by age could lead to misinterpretation. It was found that most participants with CMT presented with isometric muscular strength compatible with their body weight and height. Exceptions were found for the dorsiflexor muscles of participants C, E, and N. Normative data for comparison were not found for the foot invertor and evertor muscles nor for the plantar flexor muscles. However, it is worth noting that in 9 of the 19 participants, the muscle strength of invertors and evertors was lower than 5 KgF, which suggests a strength deficit in these muscle groups. For the participants in this study, who presented with reduced distal muscle strength, the tasks involving static balance were more affected than the tasks involving dynamic balance because static postures required greater ROM and higher torque of the ankle musculature 22. The balance deficits found in the participants of this study were not disabling, considering that the PBS score was close to the maximum (between 51 and 56). Because several factors positively or negatively affect balance 17, it is possible that mechanisms compensating for the distal muscle strength deficits were used (e.g., use of the hip strategy and upper limb assistance). Furthermore, proprioception and stabilization mechanisms, such as muscle stiffness, are key factors in the establishment of balance 23. Anticipatory control is another factor that could have been triggered by the patients to obtain static and dynamic balance control 22,23 . The positive correlation observed between the isometric muscle strength of the dorsiflexors, plantar flexors, evertors, and invertors with balance suggests that the maintenance of muscle strength of these muscle groups may positively affect balance. Ribeiro et al. 24 associated ankle muscle strength with balance in the elderly and, similar to Sundermier et al. 25, who evaluated children, corroborated the current study, concluding that plantar flexor and dorsiflexor strength was positively associated with balance. ROM and standing long jump The ROM available for a joint can also be defined as flexibility, which is an important element of physical fitness 26. Flexibility can be achieved by active muscle contraction, referred to as dynamic flexibility, or by passive motion caused by a force external to the joint. Gender, anthropometric measurements, body composition, genetic, and pathological characteristics, in addition to the growth and development processes 26, all influence flexibility. The participants with CMT in this study presented with a joint ROM with relative flexibility and a preserved motion arc, which established a weak correlation with performance in the standing long jump test. The standing long jump test results of the participants were compared to the normative data described by Condon and Cremin 16, who studied this variable in 534 children aged 4 to 15 years. The age- matched comparison with participants of the current study demonstrated that 7 (A, H, I, K, L, O, Q) of the 19 participants presented lower values than were described as normative. During the performance of the standing long jump test, the additional impulse imparted to the jump by the swinging of the arms might have increase the distance jumped and the takeoff speed 27. In this study, all participants were instructed to perform the test movement using the technique of propelling themselves with the arms. Ashbya and Heegaard 27 indicated that the arm swing enhanced the force-producing ability of the lower extremity extensor muscles, slowing the contraction speed at key moments in the jump. To maintain balance throughout the jump, measures such as anticipatory control or even the employment of counterproductive mechanisms that reduce the jumping distance with free arm motion may have been adopted 27. Considering that children with CMT are aware of their balance deficits, it is possible that they adopted anticipatory control measures using the free arms. Thus, the restricted use of the arms by certain participants may explain in part the lower jumping performance of participants A, H, I, K, L, O and Q, which was significantly lower than the overall mean of the jumps considered. The standing long jump test, while considered a motor task or skill, is a complex motor pattern that requires the coordinated performance of all body segments, where the impulse and the landing must be performed with both feet. The horizontal jump measures explosive force, is strongly correlated with  340 Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 CMT disease: balance and muscle power isokinetic measures of lower limb strength, and is indicated as a good predictor of performance in the standing long jump 10. The lack of correlation or even the weak correlation found between ROM and the standing long jump test may be attributed to the fact that most participants in this study had relatively preserved ROM in distal muscles. A group of affected participants without preserved ROM should be evaluated to assess the influence of passive ROM on the standing long jump, which was a limitation of the present study. The sample size, heterogeneity of the CMT subtypes, different levels of motor maturation, and different anthropometric characteristics are common limitations in studies of this nature. Based on anthropometric data, the participants were classified in all categories of BMI, and 21% of them were obese, which may have influenced the results. BMI does not seem to negatively affect flexibility, in contrast to propulsion tests 28. Obese individuals suffer disadvantages in more challenging balance activities, such as standing on one foot 29. For muscle strength, a recent review 30 indicated that although obese individuals presented with higher absolute values compared to their normal-weight peers, obesity had no impact on the intrinsic properties of the muscle to generate force. Thus, the interference of BMI on the data obtained in the present study was considered minimal. The results of this study may assist the physical therapist in making decisions during clinical practice because they suggest that preserved dorsiflexor and plantar flexor muscle strength is associated with better static and dynamic balance performance. Similarly, the maintenance and/or gain of joint mobility, especially of dorsiflexion through stretching, may promote good functional performance and muscle strength as demonstrated in the standing long jump test. Thus, in the treatment of children and adolescents with CMT disease, the maintenance and/or gain of strength and flexibility of the dorsiflexor and plantar flexor muscles should be prioritized. Conclusion The maintenance of distal muscle strength in children with CMT contributes to their performance of balance tasks. The losses found in passive ROM of the lower limbs seem not to have been sufficient to affect muscle strength in the horizontal long jump. Acknowledgments To Elisangela Aparecida da Silva Lizzi, who was responsible for the statistical analysis; to the patients and their guardians and to the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), process number 2012/15521-3 and 2012/15522-0, Brazil, for their support in the development of this study. References 1. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot–Marie–Tooth disease. Lancet Neurol. 2009;8:654-67. http://dx.doi.org/10.1016/ S1474-4422(09)70110-3 2. Burns J, Crosbie J, Hunt A, Ouvrier R. The effects of pes cavus on foot pain and plantar pressure. Clin Biomech. 2005;20:877-82. PMid:15882916. http://dx.doi. org/10.1016/j.clinbiomech.2005.03.006 3. Tachdjian MO. The neuromuscular system-deformities of the foot and ankle. In: Tachdjian MO. Pediatric orthopedics. 2nd ed. Philadelphia: WB Saunders; 1990. p. 1937-57. 4. Robertson DG, Fleming D. Kinetics of standing broad and vertical jumping. Can J Sport Sci. 1987;12(1):19-23. PMid:3594313. 5. Cote KP, Brunet ME, Gansneder BM, Shultz SJ. Effects of pronated and supinated foot postures on static and dynamic postural stability. J Athl Training. 2005;40(1):41- 6. PMid:15902323 PMCid:PMC1088344. 6. Maggi G, Bragadin MM, Padua L, Fiorina E, Bellone E, Grandis M, et al. Outcome measures and a rehabilitation treatment in patients affected by Charcot-Marie-Tooth Neuropathy: a pilot study. Am J Phys Med Rehabil. 2011 Aug 8;90:628-637. PMid:21681064. http://dx.doi. org/10.1097/PHM.0b013e31821f6e32 7. Rose KJ, Burns J, Wheeler DM, North KN. Interventions for increasing ankle range of motion in patients with neuromuscular disease. Cochrane Database Syst Rev. 2010;(2):CD006973. PMid:20166090. 8. Sackley C, Disler PB, Turner-Stokes L, Wade DT, Brittle N, Hoppitt T. Rehabilitation interventions for foot drop in neuromuscular disease. Cochrane Database of Syst Rev. 2009;(2):CD003908. PMid:19588347. 9. Marques AP. Ângulos articulares de membros inferiores. In: Marques AP. 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Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Delineando a pesquisa clínica: uma abordagem epidemiológica. 2ª. ed. Porto Alegre: Editora Artmed; 2003. 14. Pagano M, Gauvreau K. Princípios de bioestatística. 2ª. ed. São Paulo: Editora Thomson; 2004. 15. World Health Organization – WHO [homepage Internet]. Geneva: WHO; 2006-2013 [cited 2013 July 18]. Available from: http://apps.who.int/bmi/index. jsp?introPage=intro_3.html. 16. Condon C, Cremin K. Static Balance Norms in Children. Physiother Res Int. 2014 Mar;19(1):1-7. http://dx.doi. org/10.1002/pri.1549 17. De Weerdt W, Spaepen A. Equilíbrio. In: Durward BR, Baer GD, Rowe J. Movimento Funcional Humano. São Paulo: Manole; 2001. p. 204. 18. Kuo AD, Zajac FE. A biomechanical analysis of muscle strength as limiting factor in standing posture. J Biomech. 1993;(26):137-50. http://dx.doi. org/10.1016/0021-9290(93)90085-S 19. Horak FB, Shupert CL, Mirka A. Components of postural dyscontrol in the elderly: a review. Neurobiol Aging. 1989;10:727-38. http://dx.doi. org/10.1016/0197-4580(89)90010-9 20. Wolfson LI, Whipple R, Amerman P, Kleinberg A. Stressing the postural response: a quantitative method for testing balance. J Am Geriatr Soc. 1986;34:845-50. PMid:3782696. 21. Nyström EM, Kroksmark A-K, Beckung E. Isometric muscle torque in children 5 to 15 years of age: normative data. Arch Phys Med Rehabil. 2006;87:1091- 9. PMid:16876555. http://dx.doi.org/10.1016/j. apmr.2006.05.012 22. Robinovitch SN, Heller B, Lui A, Cortez J. Effect of strength and speed of torque development on balance recovery with the ankle strategy. J Neurophysiol. 2002;88:613-20. PMid:12163514. 23. Van der Linden MH, Van der Linden SC, Hendricks HT, Van Engelen BGM, Geurts ACH. Postural instability in Charcot-Marie-Tooth type 1A patients is strongly associated with reduced somatosensation. Gait Posture. 2010;31:483-8. PMid:20226674. http://dx.doi. org/10.1016/j.gaitpost.2010.02.005 24. Ribeiro F, Teixeira F, Brochado G, Oliveira J. Impact of low cost strength training of dorsi- and plantar flexors on balance and functional mobility in institutionalized elderly people. Geriatr Gerontol Int. 2009;9:75-80. PMid:19260983. http://dx.doi.org/10.1111/j.1447-0594.2008.00500.x 25. Sundermier L, Woollacott M, Roncesvalles N, Jensen J. The development of balance control in children: comparisons of EMG and kinetic variables and chronological and developmental groupings. Exp Brain Res. 2001;136:340- 50. http://dx.doi.org/10.1007/s002210000579 26. Melo SIL, Guth VJ, Sousa ACS, Sacomori C, Martins ACV, Lucca L. Estudo comparativo de amplitudes de movimentos articulares em crianças diferentes gêneros entre os 7 e os 12 anos de idade. Motricidade. 2011;7(1):13-20. http:// dx.doi.org/10.6063/motricidade.7(1).116 27. Ashbya BM, Heegaard JH. Role of arm motion in the standing long jump. J Biomech. 2002;35:1631-7. http:// dx.doi.org/10.1016/S0021-9290(02)00239-7 28. Dumith SC, Ramires VV, Souza MA, Moraes DS, Petry FG, Oliveira ES, et al. Overweight/obesity and physical fitness among children and adolescents. J Phys Act Health. 2010;7(5):641-8. PMid:20864760. 29. Goulding A, Jones IE, Taylor RW, Piggot JM, Taylor D. Dynamic and static tests of balance and postural sway in boys: effects of previous wrist bone fractures and high adiposity. Gait Posture. 2003;17:136-41. http://dx.doi. org/10.1016/S0966-6362(02)00161-3 30. Maffiuletti NA, Ratel S, Sartorio A, Martin V. The impact of obesity on in vivo human skeletal muscle function. Curr Obes Rep. 2013;2:251-60. http://dx.doi.org/10.1007/ s13679-013-0066-7 Correspondence Cyntia Rogean de Jesus Alves de Baptista Universidade de São Paulo Faculdade de Medicina de Ribeirão Preto Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor Avenida Bandeirantes, 3900 CEP 14049-900, Ribeirão Preto, SP, Brasil e-mail: [email protected]  342 Braz J Phys Ther. 2014 July-Aug; 18(4):334-342 Copyright ofBrazilian JournalofPhysical Therapy/Revista Brasileira deFisioterapia isthe property ofBrazilian JournalofPhysical Therapy/Revista Brasileira deFisioterapia andits content maynotbecopied oremailed tomultiple sitesorposted toalistserv without the copyright holder’sexpresswrittenpermission. However,usersmayprint, download, oremail articles forindividual use.
Physical Therapist test for muscular dystrophy in pediatrics patients
REVIEW PAPER Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors Amanda Carré 1&Candice Empey 2 Received: 6 May 2014 / Accepted: 30 June 2015 / Published online: 8 August 2015 #National Society of Genetic Counselors, Inc. 2015 Abstract Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition with degeneration of the anterior horn cells in the spinal column. Five SMA subtypes exist with classification dependent upon the motor milestones achieved. Study of the SMN1(survival motor neuron) and SMN2 genes as well as the concepts of the B2+0 ^carriers, gene conversion, de novo mutations and intragenic mutations allow for a better understanding of SMA. Detailing the carrier and diagnostic testing options further deepens the genetic counselor ’s knowledge of SMA. A review of care guidelines and research options is included as this information gives a patient a well-rounded view of SMA. Although SMA is most commonly associated with the SMN1gene, a number of spinal muscular atrophies not caused by genetic changes in this gene may be included as differential diagnoses until confirmatory testing can be completed. SMA is a complex condition requir- ing a detailed knowledge on the genetic counselor ’spartin order to explain the disorder to the patient with clarity thus facilitating increased communication and decision making guidance with the patient. Keywords Spinal muscular atrophy . Carrier screening . Diagnostic testing . Genetic counseling . Prenatal . Pediatric Introduction Spinal muscular atrophy (SMA) may present in various forms, affecting every stage of life from the affected fetus with joint contractures, to the young child who never sits independently, to the young adult who loses the ability to ambulate on his or her own. Although classified as an autosomal recessive condi- tion, the genetics of SMA are not straightforward and thus, counseling for the preconception, prenatal and pediatric setting can be confusing for both the patient and health care provider. Genetic counselors are tasked with explaining the natural his- tory, genetics, testing options, and potential outcomes of ge- netic disorders, such as SMA, to their patients. The goals for this paper are to elucidate the complex genetics of SMA and to expound on the carrier and diagnostic testing options available for SMA to aid genetic counselors in their discussions with patients and other healthcare providers. The majority of litera- ture written on SMA concerns the disorder associated with genetic changes on chromosome 5. However, other spinal muscular atrophies with similar physical findings but hetero- geneous causes are often included in the differential diagnoses until confirmatory testing can be completed for the patient. Background Clinical Description The first part of this paper will focus on spinal muscular atro- phy (SMA) as caused by genetic changes of the SMN1(sur- vival motor neuron 1) gene. Please refer to the end of the paper Electronic supplementary material The online version of this article (doi:10.1007/s10897-015-9859-z) contains supplementary material, which is available to authorized users. * Amanda Carré [email protected] 1 Department of Obstetrics and Gynecology, Drexel University College of Medicine, 216 N. Broad St, Feinstein Building 4th Floor, MS 990, Philadelphia, PA 19102, USA 2 Integrated Genetics, Laboratory Corporation of America® Holdings, Philadelphia, PA, USA J Genet Counsel (2016) 25:32 –43 DOI 10.1007/s10897-015-9859-z for discussion of spinal muscular atrophies not associated with theSMN1 gene. SMA has an estimated incidence of 1 in 10,000 live births (Prior 2008; Smith et al. 2007). It is the most common genetic cause of mortality in children under the age of two. It is the second most common fatal autosomal recessive condition af- ter cystic fibrosis in the United States (Bürglen et al. 1996; Prior 2008; Wirth 2000). SMA as associated with chromo- some 5 is typically split into five subtypes, based on the age of onset and the clinical course of the disorder. Even with the degree of separation of symptoms between the sub-types, SMA is a disorder that can be categorized as a spectrum or continuum. The five subtypes are now commonly differenti- ated by numbers (0, I, II, III, IV) (Table 1). Patients are cate- gorized into their subtype by the motor milestones they achieve. All individuals with SMA have neuromuscular find- ings due to the degeneration of anterior horn cells in the spinal cord (Bürglen et al. 1996; Prior et al. 2004; Smith et al. 2007). This loss of cells leads to symmetrical loss of muscle control and atrophy in the body, with proximal muscles most commonly being affected. The level of severity differs from the loss of muscular control needed for breathing and swallowing in Type I to loss of ambulation later in life in Types III and IV (Wirth 2000). Individuals with SMA may also experience poor weight gain, sleep difficulties, sco- liosis and joint contractures as well as restrictive lung disease, dysphasia, and constipation (Iannaccone 2007). While neuro- muscular findings are universal with SMA, intelligence levels and emotional development are not affected (von Gontard et al. 2002). Type 0 SMA is often referred to as prenatal SMA, as this type presents in utero with arthrogryposis and joint contrac- tures. There is also a lack of fetal movement (MacLeod et al. 1999 ; Prior and Russman 2013; Russman 2007). Type I SMA, also known as Werdnig-Hoffman, is the most common sub- type of SMA occurring in about 60– 70 % of SMA cases (Ogino and Wilson 2004; Ogino et al. 2004;Prior 2008). Often severe muscle weakness and hypotonia lead to fatal respiratory failure by 2 years of age. With the use of respira- tory support, life expectancy can be extended. These children never gain the ability to sit or walk independently. Sabine Rudnik-Schöneborn et al. ( 2008) reported atrial or ventricular defects occur in 75 % of type I SMA patients who only had a single SMN2 copy. Type II SMA, also called intermediate form, has an onset before 18 months of age. These children can learn to sit upright but do not walk unaided. The risk for pulmonary issues remains and life expectancy is unknown, with some affected individuals surviving to adulthood. Type III SMA is diagnosed with the onset of proximal muscle weakness after 2 years of age and was previously referred to as Kugelberg-Welander disease. Individuals with Type III of- ten have the ability to walk independently until the disease progresses. Life expectancy extends into adulthood. Finally, Type IV SMA is rarely diagnosed and is not apparent in an affected individual until adolescence or adulthood. Types 0 and I are the most severe forms of SMA, while Types III and IV lead to a later onset and a milder diagnosis. Genetics Using linkage analysis, Lefebvre et al. ( 1995) first suggested the candidate gene for SMA was located at the SMN1(survival motor neuron 1) gene on chromosome 5q13. The SMN1gene is close to the telomere of chromosome five and contains nine exons about 20 kb in length (Bürglen et al. 1996; Wirth 2000). SMA is an autosomal recessive condition most commonly ca used by a homozygous deletion of the SMN1gene. Ninety-four percent of SMA cases are caused by the homozy- gous deletion of the SMN1gene, while the other 6 % of cases are compound heterozygotes with one deleted copy of the SMN1 gene and a point mutation in the other copy (Wirth 2000 ) or patients with de novo mutations. Downstream of the SMN1 gene and nearer to the centromere of chromosome 5istheSMN2 (survival motor neuron 2) gene. The SMN2 gene differs in functionality from SMN1by a single change at position 840 which leads to an alteration in splicing, reduc- ing the amount of full protein production. SMN2contains a thymine at position 840 in exon 7, whereas SMN1contains a cytosine (Bürglen et al. 1996). Individuals in the general pop- ulation typically have two SMN1gene copies, but may have Ta b l e 1 Subtypes of SMA Age of onset Clinical presentation Type 0 prenatal most severe; presents with lack of fetal movement, arthrogryposis, joint contractures; fatal at birth unless respiratory/medical support available Type I birth to 6 months severe generalized muscle weakness and hypotonia at birth; death from respiratory failure in less than 2 years Ty p e I I 6 –12 months able to sit; unable to walk or stand without aid, life expectancy unknown Type III after 18 months of age milder form; patients learn to walk unaided but lose ambulation as disease progresses Type IV adolescence to adulthood like Type III, but rarely diagnosed Compiled from Ogino et al. 2004; Prior et al. 2004; Prior 2008; Prior and Russman 2013;Russman 2007; Wirth et al. 1999 Review of SMA for Prenatal and Pediatric Genetic Counselors 33 up to four (Smith et al.2007). Prior et al. ( 2004)reportthe SMN2 copy number in the general population typically varies from zero (10 –15 %) to three SMN2gene copies. Some indi- viduals have been found to have as many as four to five SMN2 gene copies (Prior et al. 2004; Wirth 2000). Due to the nucleotide difference between the SMN1and SMN2 genes, there is a potential for gene conversion making the SMN1 gene into a SMN2gene and vice versa (Burghes 1997; Campbell et al. 1997; Lefebvre et al.1995). For example, with gene conversion, the SMN1gene is altered so it now has a thymine at position 840. Thus it becomes a SMN2gene; how- ever, the location of the newly altered SMN2gene does not change from where the original SMN1gene was positioned near the telomere. Conversion mutation rates are the same in paternal and maternal settings at 2.07 × 10 5 (Ogino et al. 2004). The SMN1 gene is responsible for producing 80 –90 % of the SMN protein while 10 –20 % of the SMN protein is de- rived from the SMN2gene. Individuals with a homozygous deletion of the SMN1gene still have the potential for making some functional protein through the SMN2gene, although the SMN2 gene produces an abbreviated protein 90 % of the time. Therefore, this is not a disorder complicated by the complete absence of the protein, but instead it is a disorder with a critical reduction of available functional protein. The SMN protein is an omnipresent protein; however, it has increased levels in the spinal motor neurons (Wirth 2000). Additionally, homozygous deletion of the SMN2gene does not lead to a diagnosis of SMA when at least one copy of the SMN1 gene is present in an individual. However, the copy number of the SMN2gene is thought to affect the genotype/ phenotype correlation when there is a homozygous deletion of the SMN1 genes (Feldkötter et al. 2002; Wirth et al. 1999; Wirth 2000). Some studies have indicated a more severe phe- notype for SMA when an individual has homozygous SMN1 mutations and less than three copies of the SMN2gene. A milder phenotype may correlate with those who have three or more copies of the SMN2gene. Prior et al. ( 2004)suggested five or more SMN2gene copies may partially compensate for the loss of the SMN1genes, although other modifying factors are most likely present. In a study published by Prior in 2009, three milder cases of SMA did not show the expected pheno- type correlation of increased SMN2copy number. Instead a c.859G>C substitution was found possibly modifying the phe- notype. SMN2copy number alone is not diagnostic of the type of SMA an individual will have. Carrier Frequency for SMA Due to SMN1 Carrier frequency differs based on ethnicity, with the highest risk of 1 in 47 for Caucasians to the lowest risk of 1 in 72 for African-Americans (Table 2). Dependent upon ethnicity, risks of being a carrier for SMA are similar to the risks of being a carrier for cystic fibrosis. For individuals of mixed ethnicity, the ethnic background with the highest risk estimate is usually used when calculating risks for a fetus to be affected by SMA. Most carriers of SMA have a heterozygous deletion of the SMN1 gene (Wirth 2000). These carriers have no medical concerns due to their carrier status. If both parents are carriers, the risk to have an affected child is 25 % based on straightfor- ward autosomal recessive inheritance. If the carrier ’s partner has two copies of SMN1, the risk to have an affected child is less than 1 %. The risk is not zero due to four situations in which a parent can be a SMA carrier even with two SMN1copies. First, the parent may have a B2+0 ^ ca rrier status. These individuals are found to have two SMN1 copies on one chromosome and no copies of the SMN1gene on the second chromosome. B2+0 ^carriers do not exhibit symptoms of SMA as they have two SMN1copies, but they have the potential to have an affected child if they pass on the chromosome with no copies of the SMN1 gene. Approximately 3.8 –4 % of the general popula- tion is thought to be a carrier of the B2+0 ^formation (McAndrew et al. 1997; Ogino et al. 2002a). Second, gene conversion between the SMN1andSMN2 genes may random- ly occur in a gamete, thus lowering the SMN1gene count and increasing the SMN2gene count passed on to a pregnancy. This conversion would not be identified as an SMN1deletion in the parental blood. Third, there are individuals who are carriers of an intragenic mutation for SMA (Ogino et al. 2004 ; Smith et al. 2007). Finally, SMA has a de novo mutation rate with a paternal and maternal rate of 2.11 × 10 4and 4.15 × 10 5 respectively (Ogino et al. 2004). An individual with two copies of SMN1is usually consid- ered a Bnon-carrier. ^The approximate 1 % residual risk may be difficult for a Bnon-carrier ^to process. While the risk may be perceived as low by the health provider, the risk may be perceived as high by the Bnon-carrier. ^Individuals may not act on the basis of the ‘actual ’risk presented to them, but act on the basis of their perception of the risk (Marteau 1999; Meiser et al. 2000;O’Doherty and Suthers 2007; Slovic et al. 1982;Slovic 1987). For examples of various scenarios illustrating SMA carrier risk calculations, please refer to Shuji Ogino and Robert Wilson ’s 2002 paper entitled BGenetic testing and risk Ta b l e 2 Carrier frequency and detection rate by ethnicity Ethnicity Carrier frequency Detection rate Caucasian 1/47 94.8 % Ashkenazi Jewish 1/67 90.5 % Asian 1/59 93.3 % African American 1/72 70.5 % Hispanic 1/68 90.0 % Overall 1/54 91.2 % Adapted from Sugarman et al. 2012 34 Carré and Empey assessment for spinal muscular atrophy (SMA)^(located in the journal of Human Genetics) or Melanie Smith and col- leagues ’2007 paper on BPopulation screening and cascade testing for carrier of SMA ^(located in the European Journal of Human Genetics). Genetic Testing Options Carrier Screening As the most common type of carrier of SMA has only one copy of SMN1, determining the copy number of SMN1is essential to carrier screening. Dosage analysis, also called copy number analysis, is used for carrier screening. Dosage analysis determines the number of SMN1genes an individual has in total. The detection rate for carrier screening is 94 % in individuals of Caucasian descent; however, it is lower for individuals of other ethnicities (see Table 2) (Sugarman et al. 2012). Specificity of carrier screening approaches 100 % (Scheffer et al. 2000). The residual carrier risk decreases with increasing number of SMN1copies found. Limitations of using dosage analysis for carrier screening include the follow- ing: cannot distinguish between B2+0 ^carriers and B1+1 ^ non-carriers, plus it cannot detect point mutations. Additionally, the de novo germline mutation rate cannot be accounted for in carrier screening (Prior and Russman 2013). Luo et al. ( 2014) recently completed analysis on carrier screening in the Ashkenazi Jewish population. They attempted to identify deletion and duplication founder alleles in the Ashkenazi Jewish population through microsatellite analysis and next-generation sequencing. The team ’saim was to improve the accuracy of residual risk estimates and increase the number of B2+0 ^carriers detected through carrier screening. Their findings are reported in BAn Ashkenazi Jewish SMN1haplotype specific to duplication alleles im- proves pan-ethnic carrier screening for spinal muscular atrophy^ (located in the journal Genetics in Medicine). Further data is needed to help determine if Luo ’ssuggested method for expanded carrier screening for potential B2+0 ^ carriers should be included as part of the initial carrier screen or if it should be ordered as a reflex test when dosage analysis does not determine the patient to be a carrier for SMA. Please refer to appendix A for a flowchart illustrating possible testing routes seen with carrier screening for SMA in the general population when the individual being tested has no family history of SMA. Over 50 laboratories throughout the world offer carrier screening for SMA. In the past, carrier testing through labo- ratories consisted of ordering SMA carrier screening as a stand-alone screen. Clinicians now have the opportunity to order SMA carrier screening as part of a multi-disorder carrier panel. These multi-disorder panels allow for a patient to be screened for numerous genetic disorders simultaneously with one sample collection instead of multiple blood draws. The process of testing with multi-disorder panels for SMA carrier status may be through dosage analysis or via sequencing of the SMN1 gene. If ordering SMA carrier screening through a multi-disorder panel, it is important to distinguish which method the laboratory utilizes. Not all laboratories offer com- plete SMA testing, such as reflex sequencing for intragenic mutations or SMN2copy number analysis. Depending upon previously completed carrier screening or patient preference, the clinician can aid the patient in selecting stand-alone SMA carrier screening versus a multi-disorder panel. For stand-alone SMA carrier screening, sample require- ments vary between the laboratories; however, many request 4 – 10 cc of whole blood in lavender top tubes (EDTA) or yellow top tubes (ACDA). Samples are sent overnight at room temperature to the laboratory completing the testing. Turn- around time may range from 5 to 28 days, depending on the la boratory. For multi-disorder panels, sample requirements al- so vary between the laboratories. Acceptable samples may include saliva samples or approximately 10 –20 cc of whole blood in lavender top tubes (EDTA). As with stand-alone testing, samples are sent overnight at room temperature to the laboratory. Turn-around time typically is 2 weeks. Many times carrier screening occurs in a consecutive man- ner, meaning the female partner of the couple is screened first and if she is found to be a carrier for SMA, then her male partner is screened. Carrier screening can occur concurrently, with both partners of the couple having blood drawn at the same time. Concurrent testing may be advisable when there is limited time to perform screening on both members of the couple, e.g., a pregnant woman has a family history of SMA and she is close to the gestational age limitation for complet- ing a fetal diagnostic procedure such as amniocentesis. Reproductive options for carrier couples include prenatal diagnosis (see further description later in this article), gamete donation, preimplantation genetic diagnosis, termination of an affected pregnancy, placing an affected individual for adop- tion and adoption of an unaffected individual. Appropriate follow-up should be offered to additional family members when an individual is found to be a carrier for SMA. This may include offering genetic counseling and carrier screening to extended family members. Approach to Prenatal Carrier Screening Current recommendations by the American College of Medical Genetics (ACMG) include offering SMA carrier screening to all couples, regardless of race or ethnicity, before conception or early in pregnancy. The ACMG also suggests educational materials be made available to all couples, while formal genetic counseling services be made available to any- one requesting this screening. The ACMG proposes all Review of SMA for Prenatal and Pediatric Genetic Counselors 35 identified carriers should be referred for follow-up genetic counseling and offered prenatal and preimplantation diagnosis (Prior2008). Current recommendations by the American Congress of Obstetricians and Gynecologists (ACOG) do not advise preconception and prenatal screening for SMA be offered to the general population. ACOG advocates testing be offered to couples with a family history of SMA or SMA-like disease and those who request SMA carrier screening after completing genetic counseling. ACOG recommends all iden- tified carriers for SMA be referred for follow-up genetic counseling to discuss prenatal and preimplantation diagnosis, including gamete donations. ACOG suggests referral to a ge- netic counselor for patients requesting fetal testing for SMA (ACOG Committee Opinion 2009). Prenatal Diagnosis Prenatal diagnosis to determine if a fetus is affected with SMA utilizes dosage analysis of the SMN1gene from fetal DNA obtained by chorionic villi sampling or amniocentesis. Invasive prenatal diagnosis by chorionic villi sampling or am- niocentesis is most appropriate if both parents are known car- riers or if the patient is a carrier and the partner ’s status is unavailable. In most situations the mutations found in the patient and her partner will be known and proper testing for these specific mutations in the fetus can be arranged. Limitations of prenatal testing utilizing dosage analysis in- clude the following: it cannot identify intragenic mutations and the partner ’s genotypic information is necessary for a more informative result. If a patient or partner has a known intragenic mutation, sequencing analysis may be utilized on the fetal DNA sample. Laboratories performing preimplanta- tion diagnosis for SMA will also use dosage and sequencing analysis to produce embryos without SMN1mutations, an option for couples who are known carriers. Postnatal Diagnostic Testing Clinically the diagnosis of SMA is suspected in individuals with a personal history of motor difficulties and evidence of motor neuron disease on a p hysical examination. The clinical classification of SMA is based on age of onset and maximum function attained (Prior and Russman 2013). Electromyography, nerve conduction velocities, muscle en- zyme creatine kinase, and muscle histology were used more so in the past to establish a diagnosis of SMA (Hausmanowa- Petrusewicz and Karwa ńska 1986 ;Russman 2007;Wang et al. 2007). After linkage analysis was used to identify the SMN1gene, deletion analysis of the SMN1gene was used as the basis for a SMA diagnosis. Deletion analysis consists of the detection of the complete absence of exon 7 in the SMN1gene. The detec- tion rate of this diagnostic testing for an affected individual is 94– 95 % (Lefebvre et al. 1998;OginoandWilson 2002; Wang et al. 2007) with almost 100 % specificity (Rodrigues et al. 1995; Wang et al. 2007). With deletion analysis, the polymerase chain reaction-RFLP assay utilizes restriction en- zymes to cut only the SMN2exon 7 polymerase chain reaction products. In patients with spinal muscular atrophy, the uncut SMN1 exon 7 is found to be absent (Prior 2007). This type of deletion analysis is also called RFLP analysis. Currently, over 60 laboratories worldwide perform diagnos- tic testing for SMA. Deletion analysis may often be first tier testing due to cost prohibitions for the other technologies uti- lized for SMA diagnostic testing. Deletion analysis, however, cannot detect the copy number of SMN1(thus it cannot detect individuals who are carriers for SMA or compound heterozy- gotes), point mutations, and small intragenic insertions or de- letions. To address the limitations of this older technology, clinicians may choose to begin testing their patients through dosage analysis and then reflex to sequence analysis of the entire coding region, which increases the ability to identify compound heterozygote patients with intragenic mutations. Dosage analysis is a quantitative test for the number of SMN1 gene copies, while sequence analysis of the SMN1gene may be especially useful for those who are suspected of being compound heterozygotes with an intragenic mutation and de- letion of one copy of the SMN1gene (Prior et al. 2011). Sequence analysis can be performed for the detection of cer- tain intragenic mutations such as small intragenic deletions/ insertions and missense, nonsense, and splice site mutations. Whole-gene deletions/duplications may not be detected, while variants of uncertain significance may be detected. Additional testing by a method facilitating SMN1-specific and SMN2- specific amplification and sequence analysis (Prior et al. 2011 ) is necessary to verify an intragenic mutation has oc- curred in SMN1and not SMN2. McAndrew et al. ( 1997) developed the first assay for dos- age analysis of the SMN1gene. The assay uses quantitative PCR analysis. The copy number of SMN1is determined by the coamplification of SMN1,SMN2 and other gene standards. Since then, other assays of dosage have been developed. Dosage analysis allows for the detection of duplication as well as deletion of the SMN1gene, as determined by the copy number present (Ogino and Wilson 2004). This technology is most utilized for carrier status, although it can be used for diagnostic purposes, including prenatal diagnosis. Finally, some laboratories also use linkage analysis in con- junction with dosage analysis. Linkage analysis can be uti- lized when two copies of SMN1are found in the parents of an affected child who lacks both copies of SMN1(Ogino and Wilson 2002; Ogino et al. 2002b). If an intragenic mutation is found in an affected individual, linkage analysis can help track which unaffected or undiagnosed family members may have the same intragenic mutation. Chen et al. ( 1999)reportthat linkage analysis can also be useful in differentiating between 36 Carré and Empey theB1+1 ^genotype and the B2+0 ^genotype, as well as find- ing crossover events associated with de novo SMN1deletions. Appendix B includes a flowchart illustrating possible test- ing routes that may occur with diagnostic testing for SMA. For more in depth reviews of the diagnostic testing method- ology for SMA please refer to Shuji Ogino and Robert Wilson ’s 2004 paper entitled BSpinal Muscular Atrophy: Molecular Genetics and Diagnostics ^(located in the journal of Expert Review of Molecular Diagnostics) or Thomas Prior and colleagues ’2011 paper on BTechnical Standards and Guidelines for Spinal Muscular Atrophy Testing ^(located in Genetics in Medicine). When an individual has been found to have SMA through diagnostic testing, appropriate follow-up should be offered to additional family members. This includes carrier screen- ing for the parents of the affected child so reproductive options and recurrence risks for subsequent pregnancies can be established. Siblings of reproductive age also benefit from carrier screening; however, parents of siblings who are not yet of reproductive age may wish to wait until those siblings are older to pursue this testing. Diagnostic testing in siblings who may not yet be exhibiting symptoms of SMA is controversial and the implications of such testing should be discussed thor- oughly with the family before pursuing testing. The American Society of Human Genetics (ASHG) and the American College of Medical Genetics ’(ACMG) Boards of Directors in 1995 discussed numerous points to consider when testing minors for genetic disorders, including the impact of potential benefits and harms on decisions about testing, the family ’s involvement in decision making, and considerations for future research. For example, medical benefit to the child should be the main justification for completing genetic testing in minors. Therefore, some health practitioners may advise delaying test- ing in a child who is not showing signs of SMA if the medical benefits are uncertain or will not be beneficial to the child at the current time. Others contend early testing may lead to earlier treatment and therefore possibly reduce the severity of the disorder in the potentially affected individual. ASHG and ACMG stress the importance of not only focusing on the medical benefits and harms of genetic testing on minors but also the potential psychosocial benefits and harms genetic testing can involve. Extended family members, such as aunts, uncles, and cousins of reproductive age, may also be informed of the risks to be carriers. Genetic counselors can work with primary families to determine the best way to approach ex- tended family members with the information on screening opportunities. Treatment for Affected Individuals There is no genetic cure for SMA; however, a number of treatments are performed on affected individuals. The International Standard of Care Committee for Spinal Muscular Atrophy was founded in 2005 with the goal of de- veloping guidelines for care of affected individuals. The com- mittee suggests either a pediatric neurologist or geneticist co- ordinate clinical care for the patient and their family. Medical management of individuals with SMA also includes team members from genetic counseling, orthopedics, neurology, pulmonology, general surgery, gastroenterology, neonatology, general pediatrics, and palliative care. Currently treatment for SMA focuses on symptomatic and supportive care for indi- viduals with SMA. The International Committee focused on five areas of care in its guidelines for SMA –diagnostic/new interventions, pulmonary, gastrointestinal/nutrition, orthope- dics/rehabilitation, and palliative care (Wang et al. 2007). Diana Castro and Susan Iannaccone in their 2014 article B Spinal Muscular Atrophy: Therapeutic Strategies ^(located in the Current Treatment Options in Neurology journal) pro- vide further commentary on medical management for symp- tomatic patients with SMA. Treatments for the physical concerns focus on the symp- toms of the disorder. For the pulmonary concerns, Wang et al. ( 2007 ) listed the key respiratory problems as impaired ability to cough, hypoventilation during sleeping periods, underde- velopment of the chest wall and lungs, and recurrent infec- tions. Respiratory support is designed to aid individuals with breathing at times of wakefulness and sleeping. This support may include the use of ventilators with masks available in numerous sizes and maintaining airway clearance by utilizing me chanical cough assist machinery (Iannaccone 2007). Patients with SMA type I can survive beyond 2 years of age when offered tracheostomy or noninvasive respiratory support (Bach et al. 2002). Respiratory support is seen as a tool to extend the length of an affected patient ’s life, but it does not slow the progression of the disease. Families may feel respi- ratory support can improve the quality of life for their child. Gastrointestinal problems include feeding and swallowing issues, dysfunction of the gastrointestinal system including constipation, delayed gastric emptying and growth difficulties (Wang et al. 2007). With constipation concerns, dietary man- agement and control of fiber and water content may help min- imize the discomfort for the patient and reduce the risk for bowel impaction (Iannaccone 2007). Other treatments con- centrate on augmenting feeding times and increasing the nu- trients obtained during those feedings. Placement of feeding tubes may be beneficial for some patients; however, the sur- gery to place such tubes comes with risks for individuals with SMA. These risks must be discussed with the family prior to the potential need for surgery so the appropriate plan of care can be made for the patient. Monitoring for and management of gastroesophageal reflux is also important for individuals with SMA as it can increase the mortality and morbidity rates in this population due to risks for aspiration, pneumonias and additional respiratory concerns (Birnkrant et al. 1998; Wang et al. 2007). Review of SMA for Prenatal and Pediatric Genetic Counselors 37 Orthopedic care includes conservative and operative treat- ment options for contractures, hip dysplasia, fractures, scoliosis and pelvic obliquity. One of the major problems in orthopedic therapy is scoliosis in nearly 100 % of nonambulatory SMA patients with type II and III (Haaker and Fujak 2013). Surgical spine correction can result in rest ored sitting ability without arm support and avoidance of impingement of the ribs on the pelvis creating increased sitting comfort and self-confidence in en- hanced appearance (Haaker and Fujak 2013). Treatments also include physical therapy, occupational therapy, orthoses, tech- nical devices, operative treatment, power wheelchairs for mo- bility, and pain management. Finally, palliative care with the use of hospice referrals and availability of medical, social, and spiritual assistance can benefit families (Wang et al. 2007). A debate exists concerning the current available therapies that may prolong the length of life, but do not increase the quality of life (i.e., do not slow the progression of the disease). There is little agreement in the literature about the use of available treatments and optimal care for patients with SMA. Optimal management is achieved through a multidisciplinary approach with consistent communication between the medical team and the patient ’sfamily. Emerging Medical Therapies Due to the inability to effectively slow the progression of the disorder with current treatments, a number of research teams are exploring methods to treat affected individuals to slow or stop progression of the disorder. In Li-Kai Tsai ’s 2012 review article, therapy development can be divided into two classes; B SMN Dependent ^and BSMN Independent ^targets. In poten- tial SMN dependent therapy the strategies are divided into small molecules, antisense oligonucleotides and viral vector mediated gene therapy. The aim of small molecules, which include histone deacetylase inhibitors such as aclarubicine (Andreassi et al. 2001), sodium butyrate (Chang et al. 2001), and valproic acid (Brichta et al. 2003), is to increase the level of full-length proteins as made by the SMN2gene. Pfizer (234 East 42nd Street, New York, NY 10017) is conducting phase I studies researching the ability of quinazolines to prohibit the breakdown of SMN2RNA (Castro and Iannaccone 2014; Zanetta et al. 2014a). However, most small molecule therapies have not proven to show consistent benefits in clinical trials (Kissel et al. 2011; Swoboda et al. 2009, 2010 ; Tsai 2012). Antisense oligonucleotides (ASO) are designed to base pair with target RNA. ASO can then elicit effects on the RNA, such as promoting RNA degradation, interfering with pre-mRNA pro- cesses, blocking access to RNA an d disrupting the structure of the RNA (Rigo et al. 2012; Zanetta et al.2014b). The process through which the ASO works is dependent upon the class of RNA, the location on the RNA the ASO binds, and the chemical composition of the ASO itself (Rigo et al. 2012). Rigo et al. ( 2012)showedsystemictreatme nt with ASOs could enhance survival in a mouse model with severe SMA. ISIS Pharmaceuticals Inc. (2855 Gazelle Court, Carlsbad CA 92010) is in the process of testing an ASO therapy (ISIS- SM NRx) that allows the nucleotides to bind to the mRNA se- quence in the SMN2gene. Then exon 7 of the SMN2gene is able to be included in the sequencing instead of being repressed; thus, a full length and more functional SMN protein is created (Castro and Iannaccone 2014; Zanetta et al. 2014a,b). In mice and non- human primates, the use of ISIS-SMNRx, a 2 ′-O-Methoxyethyl- modified antisense drug, has shown the ability to increase the production of fully functional SMN protein (Rigo et al. 2014). In the ISIS clinical trial phase I study, patients with types II and III SMA were injected with an ASO into their intrathecal space, thus allowing for a bypass of the blood brain barrier and ensuring the drug can have an effect in the central nervous system (Castro and Iannaccone 2014). A phase II study is currently underway de- signed to examine the safety, tole rability and pharmacokinetics of multiple dose administration (Zanetta et al. 2014a). Braun ( 2013) describes a possible limitation of ASO use in treating patients with SMA. He notes re-administration of the ASO would be necessary due to the limited half-life of the compound. Viral vector mediated gene therapy in animal trials involves injection of a viral vector carrying SMNinto mice with SMA. Glascock et al. ( 2011) found when injecting a viral vector with SMN intracerebroventricularly into SMA mice, they gained more weight and displayed fewer early deaths than mice injected intravenously thus demonstrating route of delivery of vector mediated gene replacement is crucial in gene therapy treatment for SMA. In 2014, a phase I clinical trial began at Nationwide Children ’s Hospital in Ohio. The study is investi- gating the ability of an adenovirus vector, AAV9, to cross the blood brain barrier and replace the missing SMN1gene in patients with SMA (Castro and Iannaccone 2014; Zanetta et al. 2014b ). Viral gene therapy has shown an advantage of having a long survival time in preclinical studies with the need for only one delivery (Braun 2013). Another new SMNdependent therapy being evaluated is the idea of neuroprotection. Trophos, a French pharmaceutical company, recently conducted a phase II study concerning the ability of olesoxime to provide protection for motor neurons. The therapy was found to be effective in keeping motor neu- rons alive in culture (Zanetta et al. 2014a). Olesoxime was provided orally to patients with SMA II or III. The goal was to determine if the medication, a cholesterol-like molecule, could also aid the survival of motor neurons in human sub- jects. At this time, no results of the phase II study are available for review (Castro and Iannaccone 2014; Zanetta et al. 2014a). SMN independent potential therapies include but are not limited to myotrophic effects, axonal dynamics, and stem cells. Investigation of albuterol is an example of a potential therapy involving myotrophic effects. A trial with 23 type II SMA patients showed better Hammersmith motor functional 38 Carré and Empey scores after daily treatment for 6 or 12 months (Pane et al. 2008). With reference to axonal dynamics, treatment of SMA model mice with Rho-kinase inhibitor Y-27632 led to signif- icant prolonged survival and improvement in the integrity of neuromuscular junctions (Bowerman et al. 2012; Tsai 2012). Stem cell therapy includes neural stem cells, embryonic stem cells and induced pluripotent stem cells. Kerr et al. ( 2003 ) researched the ability to use stem cell therapy to estab- lish motor neurons to replace those which degenerated due to the disease. Corti et al. ( 2008) used intrathecal injection of neural stem cells derived from mouse spinal cord into a severe type of SMA mouse model. This therapy showed promoted motor neuron survival, improved motor function and prolonged lifespan. There is much still to be accomplished in cell therapy before clinical application is possible (Tsai 2012). For more intensive reviews of current and future medical therapies for SMA, please refer to the 2013 article BGene- based therapies of neuromuscular disorders: an update and the pivotal role of patient organizations in their discovery and implementation (Serge Braun, The Journal of Gene Medicine), ^Chiara Zanetta ’s2014article BMolecular thera- peutic strategies for spinal muscular atrophies: current and future clinical trials (Clinical Therapeutics journal), ^and the 2014 article from Journal of Cellular and Molecular Medicine by C. Zanetta BMolecular, genetic, and stem cell-mediated therapeutic strategies for spinal muscular atrophy. ^Through ongoing research, treatments may soon be designed to signif- icantly reduce the severity of symptoms associated with SMA. For patients wishing to participate in research, an up-to-date list of ongoing trials for spinal muscular atrophy can be found at www.clinicaltrials.gov . At the time of the writing of this paper, there were 160 studies registered for SMA testing. Other Types of Spinal Muscular Atrophies When an individual with symptoms suggestive for SMA pre- sents for clinical examination with no confirmed genetic di- agnosis, numerous genetic disorders may be considered in the differential diagnosis. Some of these genetic disorders may include forms of SMA unrelated to changes in the SMN1gene. The following is a short review of a number of different spinal muscular atrophies included in the differential diagnosis list. This list is not all inclusive. SMA with respiratory distress type 1 (SMARD) is another autosomal recessive condition. It is linked to the IGHMBP2 gene at 11q13.2-q13.4. Affected individuals present in the first 3 months of life with eventration of the right or both hemidiaphragms plus finger and feet abnormalities (Wang et al. 2007). X-linked infantile SMA with arthrogryposis is also associ- ated with loss of anterior horn cells in the spinal cord (Baumbach-Reardon et al. 2012). X-linked infantile SMA, however, has been linked to a change at Xp11.3-q11.2. For affected children, death can occur at less than 2 years of age (Wang et al. 2007). The disorder is associated prenatally with polyhydramnios and poor fetal movement, which can lead to bone fractures. After delivery, these children face restrictive lung disease (Baumbach-Reardon et al. 2012). X-linked spinal and bulbar muscular atrophy is a disorder seen in men, with an onset between 20 and 50 years of age. These affected individuals show muscle weakness, muscle atrophy, fasciculations, gynecomastia, testicular atrophy, and reduced fertility (La Spada 2011; Russman 2007). Carrier fe- males for X-linked spinal and bulbar muscular atrophy may experience muscle cramps or tremors (Mariotti et al. 2000). Autosomal dominant SMA typically has an onset after 20 years of age; however, there are a few cases of adolescents with autosomal dominant SMA. This slowly progressing disor- der comprises up to 30 % of adult onset SMA (Pearn 1978 ; R ietscheletal. 1992). As a specific example of an autosomal dominant SMA, individuals with scapuloperoneal spinal muscu- lar atrophies experience a loss of ambulation occurring in the fifth decade or later. A linkage analysis of one large affected family suggests a change in the area of 12q24.1 –24.31 to be the causa- tive factor (Isozumi et al. 1996). These disorders are diagnosed through the presence of large motor units on electromyography with normal sensory potentials and normal nerve conduction velocities (Russman 2007). They clinically present with progres- sive weakness of scapuloperoneal and laryngeal muscles (Wang et al. 2007). Distal spinal muscular atrophies, unlike SMN1-associated SMA which starts in the proximal muscles, are classified as such due to the wasting of the distal muscles with slow pro- gression to the proximal muscles (Russman 2007). There are currently ten subtypes of distal spinal muscular atrophy, with both autosomal dominant and autosomal recessive methods of inheritance noted (Irobi et al. 2004). Individuals with later-onset autosomal recessive hexosa- minidase A, or G M2 -gangliosidoses, deficiencies have been incorrectly identified as affected by SMA. Case reports have discussed how affected individuals were found to meet the clinical diagnosis of SMA –difficulty in ambulation, progres- sive decline in muscle strength, SMA electromyography find- ings, and SMA muscle biopsy findings. However, when fur- ther tested for hexosaminidase A activity levels, the patients were found to be lacking normal levels of hexosaminidase A and were thus diagnosed with hexosaminidase A deficiencies (Johnson et al. 1982; Karni et al. 1988). Pontocerebellar hypoplasia with SMA is an autosomal reces- sive condition, caused by a mutation in the VRK1gene, present- ing with cerebellar and brainstem hypoplasia and neuronal loss in the basal ganglia (Renbaum et al. 2009;Wangetal. 2007). Fazio-londe disease affects the lower cranial nerves and symptoms become apparent in the second decade of life. Death usually occurs within 1 to 5 years of the diag- nosis (Russman 2007). Review of SMA for Prenatal and Pediatric Genetic Counselors 39 Summary There is substantial variability in the natural history of SMA as it is a complex genetic disorder with numerous subtypes and dif- ferential diagnoses. The focus of this paper has been on spinal muscular atrophy as caused by genetic changes in theSMN1gene on chromosome 5q13. This overv iew of the current literature provides a comprehensive summary of the disorder, including the natural history of the disorder, the genetics of SMA, available carrier screening, potential prenatal and pediatric diagnostic test- ing, care management options, pot ential emerging medical treat- ment therapies, and differential diagnoses. Healthcare providers, especially genetic counselors, may routinely be called upon to discuss SMA with their patients as the general public becomes aware of the availability of carri er screening for this disorder. Genetic counselors are in the ideal position to be educational resources on SMA. They may provide pertinent, factual medical information and support materials to their patients. In relation to the natural history of SMA, there are five subtypes of SMA. They are clinically denoted by the motor milestones achieved by the affected individual. All five sub- types share a main diagnostic feature –degeneration of the anterior horn cells in the spinal column; however, age of onset of the symptoms plays a role in the categorizing of the subtype an individual has. Numerous items complicate the inheritance pattern and counseling for SMA. The numerical count of SMN1and SMN2 genes an individual carries is one such issue. Prenatal and pediatric genetic counseling for SMA referrals may need to involve discussion of B2+0 carriers, ^gene conversion be- tween the SMN1andSMN2 gene, maternal and paternal de novo mutations, and intragenic mutations. Without a genetic cure for SMA, care has been focused on providing symptom- atic and supportive treatments for patients with SMA. Great advances in clinical research trials have placed potential treat- ments on the horizon which aim to reduce the severity and progression of SMA. Finally, a subset of spinal muscular at- rophies not caused by deletions or intragenic changes in the SMN1 gene exists. These disorders are often included in the differential diagnoses for a suspected affected individual until confirmatory diagnostic testing can be completed. Resources Healthcare Provider Resources GeneReviews: http://www.genetests.org/resources/ genereviews.php GeneTests: http://www.genetests.org/ OMIM (online Mendelian Inheritance in Man): http:// www.omim.org/ Appendix C : Sample letter for carrier of SMA to share with family members Appendix D : Sample letter for parents of child with SMN1 gene deletions to share with family members Appendix E : Sample letter for parents of child with SMN1 gene deletion and intragenic mutation to share with family members Patient and Family Resources The Claire Altman Heine Foundation, Inc. 1112 Montana Ave, #372, Santa Monica CA 90403 www.clairealtmanheinefoundation.org Cure SMA 925 Busse Road, Elk Grove Village IL 60007 www.curesma.org Fight SMA 1321 Duke Street, Suite 304, Alexandria VA 22314 www.fightsma.org The Jennifer Trust 40 Cygnet Court, Timothy ’s Bridge Road, Stratford upon Avon, Warwickshire CV37 9NW, U.K. www.jtsma.org.uk Muscular Dystrophy Association –USA National Headquarters 3300 E. Sunrise Drive, Tucson AZ 85718 www.mdausa.org Spinal Muscular Foundation 888 Seventh Avenue, Suite 400, New York NY 10019 www.smafoundation.org Acknowledgments We would like to thank Kenny Wong, Meghan Wayne, Patricia Page and Natalie Beck for their help in gathering data for this paper. We also gratefully thank Dr. Alan Donnenfeld and Dr. Geraldine McDowell for their review of this manuscript. Compliance with Ethical Standards Please refer to this section which is located on page 33. It contains the conflict of interest statements, re- search involving human/animal participants ’statement, and the informed consent statement. Conflict of Interest Amanda Carré declares that she has no conflict of interest. Candice Empey was a past employee of Integrated Genetics, Laboratory Corporation of America® Holdings, which performs Spinal Muscular Atrophy testing. Research Involving Human Participants and/or Animals This arti- cle does not contain any studies with human participants or animals per- formed by any of the authors. Informed Consent As this article does not contain any studies with hu- man participants or animals, informe d consent was not necessary to obtain. Comments This manuscript is submitted solely to the Journal of Genetic Counseling and has not been published elsewhere or submitted to any other journal for publication purposes. 40 Carré and Empey Appendix A Appendix B References ACOG Committee Opinion No. 432. (2009). Spinal muscular atrophy.Obstetrics and Gynecology, 113 , 1194–1196. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. (1995). ASHG/ ACMG report: points to consider: ethical, legal and psychosocial implications of genetic testing in children and adolescents. American Journal of Human Genetics, 57 ,1233–1241. 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Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of Prenatal General Population Carrier Screen Flowchart Carrier screen for patient with no family history of SMA Patient found to have 2 copies of SMN1 No further testing needed Patient found to have only 1 SMN1 copy Partner tested and has 2 copies of SMN1 Risk reduced to have an affected child, can discuss sequencing to further reduce carrier risk for partner if concerns remain for SMA Partner tested and has 1 SMN1 copy Prenatal diagnostic testing (CVS or amniocentesis) Postnatal diagnostic testing Options counseling if results confirm SMA diagnosis * Genetic counseling can occur at any step in this process Fig. 1 Prenatal general population carrier screen flowchart Pediatric Diagnostic Testing Flowchart Suspected SMA SMN1 dosage analysis Homozygous SMN1 deletion SMA diagnosis confirmed 2 copies of SMN1 found Consider SMA differentials No intragenic mutation found SMN1 sequence analysis Intragenic mutation identified 1 copy of SMN1 found Fig. 2 Pediatric diagnostic testing flowchart Review of SMA for Prenatal and Pediatric Genetic Counselors 41 spinal muscular atrophy.Biochemical and Biophysical Research Communications, 417 ,376–381. 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Quantitative analysis of survival motor neuron copies: identification of subtle SMN1mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. American Journal of Human Genetics, 64 ,1340–1356. Zanetta, C., Nizzardo, M., Simone, C., Monguzzi, E., Bresolin, N., Comi, G., & Corti, S. (2014a). Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clinical Therapeutics, 36 ,128–140. Zanetta, C., Riboldi, G., Nizzardo, M., Simone, C., Faravelli, I., Bresolin, N., Comi, G., et al. (2014b). Molecular, genetic and stem cell- mediated therapeutic strategies for spinal muscular atrophy (SMA). Journal of Cellular and Molecular Medicine, 18 ,187–196. We began our research for this paper by conducting multiple PubMed searches. These searches were completed to locate papers included in the reference section. Keyword combinations utilized during the searches included: spinal muscular atrophy, spinal muscular atrophy carrier screen- ing, and spinal muscular atrophy diagnostic testing. No publishing date limitations were used during the searches. A review of the reference sections in the papers found through the PubMed searches allowed for the collection of additional publications. Finally, a search for spinal mus- cular atrophy on GeneTests ( http://www.genetests.org/ ) demonstrated numerous differential diagnoses for spinal muscular atrophy as caused by changes in the SMN1gene. Review of SMA for Prenatal and Pediatric Genetic Counselors 43 Copyright ofJournal ofGenetic Counseling isthe property ofSpringer Science&Business Media B.V.anditscontent maynotbecopied oremailed tomultiple sitesorposted toa listserv without thecopyright holder’sexpresswrittenpermission. However,usersmayprint, download, oremail articles forindividual use.