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Characterization of gait in late onset Pompe disease
Molecular Genetics and Metabolism 116 (2015) 152–156
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Characterization of gait in late onset Pompe disease Paul T. McIntosh ⁎, Laura E. Case, Justin M. Chan, Stephanie L. Austin, Priya Kishnani Duke University Medical Center, DUMC 103857, 905 La Salle, GSRB1, 4th Floor Durham, NC 27710
a r t i c l e
i n f o
Article history: Received 1 September 2015 Accepted 1 September 2015 Available online 5 Deptember 2015 Keywords: Pompe disease Neuromuscular disease GAITRite Gait analysis Temporospatial parameters
a b s t r a c t The skeletal muscle manifestations of late-onset Pompe disease (LOPD) cause significant gait impairment. However, the specific temporal and spatial characteristics of abnormal gait in LOPD have not been objectively analyzed or described in the literature. This pilot study evaluated the gait of 22 individuals with LOPD using the GAITRite® temporospatial gait analysis system. The gait parameters were compared to normal reference values, and correlations were made with standard measures of disease progression. The LOPD population demonstrated significant abnormalities in temporospatial parameters of gait including a trend towards decreased velocity and cadence, a prolonged stance phase, prolonged time in double limb support, shorter step and stride length, and a wider base of support. Precise descriptions and analyses of gait abnormalities have much potential in increasing our understanding of LOPD, especially in regards to how its natural history may be modified by the use of enzyme replacement therapy (ERT) and other interventions. Gait analysis may provide a sensitive early marker of the onset of clinical symptoms and signs, offer an additional objective measure of disease progression and the impact of intervention, and serve as a potentially important clinical endpoint. The additional data from comprehensive gait analysis may personalize and optimize physical therapy management, and the clarification of specific gait patterns in neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Pompe disease (Glycogen storage disease type II, GSDII, OMIM # 232300 or acid maltase deficiency) is an autosomal recessive neuromuscular disorder characterized by a deficiency of functional lysosomal enzyme acid α-glucosidase (acid maltase, GAA, OMIM *606,800, EC 3.1.26.2), secondary to mutations in the GAA gene (HGNC:4065) on chromosome 17q25.2-q25.3 [1]. Over time, intra-lysosomal accumulation of glycogen occurs in many tissues, most significantly within skeletal, cardiac, and smooth muscle cells, leading to muscle damage and myopathy [2]. The disease has a broad clinical spectrum ranging from a severe infantile form with generalized hypotonia and hypertrophic cardiomyopathy, to a slowly progressive proximal myopathy with skeletal muscle and respiratory dysfunction in late onset Pompe disease (LOPD) [2]. Newborn screening in Taiwan indicates that the prevalence of the disease may be as high as 1:17,000, although this statistic may disproportionately represent the infantile population since the phenotype is not yet well established [3]. The skeletal muscle weakness in LOPD predominantly manifests proximally with primary involvement of trunk and pelvic girdle
⁎ Corresponding author. E-mail addresses: [email protected], [email protected] (P.T. McIntosh).
http://dx.doi.org/10.1016/j.ymgme.2015.09.001 1096-7192/© 2015 Elsevier Inc. All rights reserved.
musculature with variation in the rate of progression, distribution, and extent of muscle damage [4,5]. The most commonly affected muscle groups in LOPD are the spinal extensors, abdominal muscles, and pelvic girdle muscles [5]. The diaphragm is involved resulting in respiratory compromise and can be selectively involved early in the disease progression. Altogether, the skeletal muscle dysfunction and respiratory problems can lead to dependency on a wheelchair and/or mechanical ventilation. The initial clinical complaints by individuals with LOPD are often related to impaired motor function. Depending on the particular weaknesses and muscle imbalances, individuals may have graded difficulties with activities such as running, climbing stairs, getting out of a chair, and rising from the floor [6]. Patients with LOPD are often caught in a self-perpetuating cycle as the progressive imbalanced muscle weakness, the resulting compensatory movement patterns and postural habits, and the influence of gravity all interact in the progression of motor dysfunction, leading to eventual reliance on mobility assistive devices for ambulation [5]. Ambulation difficulty has been well documented in LOPD, and as much as 87% of the LOPD population experience mobility issues without enzyme replacement therapy (ERT) [6]. However, specific gait characteristics of LOPD are mentioned very little in current literature. The gait in LOPD has simply been described as a waddling gait with a possible presence of lumbar hyperlordosis [7]. To our knowledge, the characteristics of abnormal gait patterns in LOPD have never been
P.T. McIntosh et al. / Molecular Genetics and Metabolism 116 (2015) 152–156
153
quantitatively evaluated. The aim of this study was to collect objective measurements of LOPD patients' gait and to evaluate gait deviations as compared to norms. To this end, we used the GAITRite® (www. gaitrite.com) portable temporospatial gait analysis system to offer initial quantification of gait characteristics of individuals with LOPD.
session by a trained physical therapist. Three of the subjects walked with an assistive device, whereas the other nineteen subjects walked unaided along the mat.
2. Subjects and Methods
The gait cycle is defined as the movement from one foot strike to the subsequent foot strike on the ipsilateral side. It is composed of two primary phases: (i) the stance phase in which the foot is in contact with the ground, and (ii) the swing phase in which the foot is in the air. Bilateral analysis of coordination between these phases considers double limb support versus single limb support [11]. Gait analysis can measure other temporal variables of gait including step time, cadence, and velocity as well as the distance variables of step/stride length and heel-to-heel base of support.
2.1. Subjects The study was performed at Duke University Medical Center in Durham, North Carolina under an IRB approved study; consent was documented for each participant. Inclusion criteria for participation were: 1) confirmation of LOPD with gene mutation analysis and/or enzymatic assay; 2) ability to independently walk at least 10 m with or without the aid of an ambulatory assistance device. Twenty-two individuals with LOPD were included in the study (mean age 48.6 (range 13–72) years). Demographics in Table 1. All of the patients were Caucasian and on ERT at the standard dose of 20 mg/kg every 2 weeks (range 1–10 years; mean 4.2 years) at the time of the study. 2.2. Methods The GAITRite® gait analysis system, consisting of a computer with the GAITRite® software connected to the pressure-sensing GAITRite® electronic portable walking mat, was used for characterization of temporospatial parameters of gait. For the purposes of this study, we focused on gait velocity, cadence, step and stride length, which are directly affected by height, heel-to-heel base of support, and the percentage of time spent in single limb support, double limb support, and swing and stance phases of the gait cycle. The GAITRite® software-generated Functional Ambulation Profile (FAP) is an integrated numerical composite score of gait function, and its reliability has been well documented with values of 0.902–0.970 for test-retest reliability and 0.945–1.000 for inter-rater reliability [8–10]. For each subject in this study, the age, height (cm), body mass (kg), gender, and bilateral lower extremity lengths (cm) were recorded. For each trial, each subject walked barefoot along a mat at a self-selected normal paced speed. These trials were collected after a 2 h clinical
Table 1 Demographics. Study ID Gender Age at GAITRite® Number Assessment (years)
Approximate Time (years) on ERT at GAITRite® Assessment
Use of ambulatory aids
6MWT (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
7 1 1.5 8 7 1.5 5 5 3 1.5 1.5 3 10 2 N/A 2.5 5.5 4 3.5 3.5 7 7
Yes None Yes Yes None Yes Yes None Yes None None None Yes None Yes None Yes None Yes None None Yes
86.63 109.89 90.7 51.16 90.56 74.94 49.97 81.1 92.23 102 58.02 74.23 33.89 96.95 39.4 75.61 64.01 82.46 58.71 53.23 65.92 41.09
F F F F M M F M M M F M M F M F F M M M F M
49 30 72 53 61 55 52 13 66 23 18 50 63 39 60 44 60 52 59 46 61 44
2.3. Gait analysis
2.4. Statistical methods A descriptive statistic was performed for the collected data to determine the distribution and variability in the recorded parameters among the subjects. The data was compared to standardized norms from the literature [12,13]. Normative data for some gait measurements were for ages 20–60; given the age range of this cohort (maximum age 72 years), additional sources for older adults were consulted to ensure appropriate standards for which to compare this cohort [14, 15]. To aid in the comparison of each subject's bilateral (left and right) parameters to the reference ranges, we averaged the left and right values for each parameter and used the resulting single value to determine whether or not the subject fell within or outside of the reference ranges for that parameter. Correlations were made between gait abnormalities and other measures of disease progression using the Pearson product–moment correlation test. 3. Results This study provides descriptive measurements for temporal and spatial parameters of gait compared to normative data, as seen in Table 2. Of note, velocity and cadence were compared to age- and gender-matched healthy reference data. Individual discrepancies from the norm are displayed in Table 3. There was a positive relationship between the FAP score and each individual's performance on the six minute walk test (6MWT) (r = 0.67, p b .05) and on the 10 m fast walk velocity measurement (r = 0.67, p b .05). There was a very strong positive relationship between the performance on the 6MWT and gait velocity (r = 0.79, p b .05) and cadence (r = 0.86, p b .05). Additionally, there was a strong negative relationship between the 6MWT and the percentage of the gait cycle spent in double support (r = −0.70, p b .05). There was not a statistically significant correlation between age and velocity (r = −0.25), cadence (r = −0.24), performance on the 6MWT (r = −0.25) nor the FAP score (r = −0.32), which is consistent with the heterogeneous presentation of LOPD and previous reports that clinical symptoms of LOPD correlate less with age than with disease duration as reflected by time since first symptom onset [16]. 4. Discussion When compared to norms, the LOPD population demonstrated several temporal gait discrepancies secondary to lower extremity and trunk muscle weakness causing decreased stability in single limb support and difficulty during swing. This results in a slower walking speed with increased time in double limb support, the most stable period of the gait cycle. Thus the preferred speed of the LOPD population was slower than that of the references. There were also spatial gait discrepancies in the LOPD population when compared to norms. LOPD exhibited shorter stride length, likely
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Table 2 The averaged gait parameters in the LOPD population compared to reference data.* Parameters
Normal Reference Range [12,13]
Average in LOPD
Percentage of subjects outside the normal range
Standard Error
Standard Deviation
Range
velocity (cm/s) cadence (steps/min) step time (s) cycle time (s) step length (cm) stride length (cm) 2 heel-to-heel base of support (cm) time in single support (%) time in double support (%) time in swing phase (%) time in stance phase (%) FAP score
gender/age specific gender/age specific 0.53–0.59 1.06–1.18 58–85 116–170 5–10 38% - 42% 16% - 24% 36% - 44% 56% - 64% 95–100
101.6 94.7 0.66* 1.31* 63.4 127.5 10.6* 35.7%* 28.7%* 35.7%* 64.3%* 88.7*
64% below reference 95% CI 95% below reference 95% CI 68% below 68% below 32% below 27% below 64% above and 4.5% below 64% below 59% above 32% below 32% above 48% below
6.4 3.5 0.03 0.06 2.6 5.0 0.9 1.1 2.2 1.1 1.1 3.9
30.1 16.5 0.13 0.30 12.2 23.6 4.3 5.1 10.2 5.2 5.2 18.03
112.8 70.3 0.56 1.35 52.6 106.6 19.1 22.3 44.2 23.7 23.6 54
* - indicates outside of norms. Essentially all of the averaged values for the measured parameters in the LOPD population were abnormal except for step and stride length. However, the step length was asymmetrical by more than 4.5 cm in 7 subjects (32%) and 2 subjects (9%) had an asymmetric step length of more than 17 cm. The FAP score, a numerical composite score of gait status, was lower in the LOPD population when compared to normative data indicating decreased gait proficiency.
due to muscle weakness in hip flexors, hip extensors, and ankle plantar flexors. The heel-to-heel base of support tended to be greater in the LOPD population, possibly attributed to the increased stability provided by a wide base of support. One subject has significant mobility impairment, with substantial hip abductor weakness leading to decreased abduction during swing with resultant decreased base of support. The spatial parameters of gait are dependent on height; however the height of the tested population was comparable with a typical US population, except for one 13 year-old patient. In the clinic, gross motor function is evaluated comprehensively with measures of isolated muscle strength, assessment of muscle through timed functional tests and other standardized assessments, and kinematic analysis of individual tasks such as gait. The additional data from comprehensive objective gait analysis may help identify muscles contributing to mobility issues and improve the management of each patient's physical therapy needs. Sub-maximal exercise has been suggested to benefit individuals with LOPD receiving ERT [5,17]. With insight from gait analysis, improved intervention may be possible to preserve optimal body composition, strength, and mobility. Systematic gait analysis is a potential clinical endpoint to use in conjunction with the 6MWT to track disease progression and the
efficacy of therapy. The 6MWT assesses cardiac, pulmonary, circularity, and muscular capacity to provide a measure of functional ability in task performance [18]. It is a useful primary endpoint in the assessment of disease status and patient response to ERT, but additional outcome measures are needed because the current effect of intervention in LOPD is difficult to evaluate due to the heterogeneous phenotype and patterns of response [19]. Gait analysis could aid in the objective evaluation of treatment outcomes, and longitudinal data may serve as a sensitive endpoint that could assess emerging signs and symptoms, disease status, and to detect subtle changes over time [20]. The GAITRite® gait analysis system has been found to be a useful measure of disease progression in Niemann-Pick disease type C and has been investigated as a means to track the effect of ERT in MPS II patients [21,22]. It must be noted that both studies for NPC and MPS II were conducted on pediatric patients, and both MPSII and NPC have additional neurological complications other than muscle weakness than can affect ambulation, such as stiffness, central ataxia, dystonia, and seizures. However, these pediatric studies suggest temporospatial gait analysis could be extended to ambulatory individuals with infantile Pompe disease to monitor disease progression and response to treatment.
Table 3 Gait parameters outside the normal range and performance on several measures of disease progression, with the subjects being ordered by decreasing performance from expected on the six minute walk test (6MWT). Patient number Parameters velocity cadence step time cycle time step length step length differential (N4.5 cm) stride length base of support single support % double support % swing % stance % FAP score 6MWT (% predicted) 10 m fast walk (m/s) GMFM Total (%)
2
10
14
x
x
x
x
9
3
x
x
5
1
x x x x
x x
x x x x x
x
8
16
x x
x x x x
6
12
x x x
x x x
21
x x x x
x
17
x x x x
19
x x x x
11
x x x x
20
x xxx x x x
x x x x x x x x x x x x x x x N/A x 110 102 97 92.2 90.7 90.6 86.8 82.5 81.1 75.6 74.9 74.2 65.9 1.92 2.2 NA 1.92 1.47 1.43 1,79 1.64 1.75 1.32 1.79 1.43 1.05 100 100 N/A N/A N/A N/A 80.5 94.31 N/A 94.31 64.6 94.5 87.41 x
x x x x
18
x x x
4
xxx xxx x x x x
7
22
x x x x x
xxx xxx x x x x
15
xxx xxx x x x x
13
xxx xxx x x x
x x x x x x x x (−) x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 64 58.7 58 53.2 51.2 50 41.1 39.4 33.9 1.11 1.23 1.96 1.16 1.00 1.00 0.91 0.82 0.67 85.04 90.61 98 50.52 N/A N/A N/A 50.98 71.59 x x x
x x x
The data for the 6MWT, the 10 m fast walk velocity, and the GMFM were all collected on the day of the gait assessment. x - indicates a discrepancy from normal; xxx - indicates a substantial discrepancy with regards to velocity and cadence normative value; (−) - indicates an abnormal negative value for base of support.
P.T. McIntosh et al. / Molecular Genetics and Metabolism 116 (2015) 152–156
Recognizing gait patterns common in LOPD through gait analysis may facilitate timely diagnosis of the disease. The varied and initially nonspecific nature of the early signs and symptoms of this rare disease often results in delayed diagnosis. Additionally, LOPD shares many symptoms with a variety of other neuromuscular disorders, particularly the limb-girdle muscular dystrophies, causing frequent misdiagnosis. These two factors greatly delay accurate diagnosis with the mean delay to diagnosis reported to be 8 to 10 years [23]. Early diagnosis and prompt treatment initiation is critical to slow the progression in this disease, and a discrepancy in ambulatory status could be one of the first signs to present [24]. The presentation of LOPD is quite heterogeneous, but our results suggest that a decreased cadence and velocity are common and can be measured in the clinic without specialized equipment. Further and more comprehensive study of gait characteristics in a larger cohort of LOPD and other neuromuscular diseases would be beneficial in identifying signs suggesting specific diagnostic evaluation. Comprehensive gait analysis has been performed in other neuromuscular disorders including Duchene muscular dystrophy, facioscapulohumeral muscular dystrophy, and spinal muscular atrophy II [25,26]. There are many strengths and weaknesses to utilizing temporospatial gait analysis in the setting of neuromuscular diseases with many implications. The strengths of temporospatial gait analysis are that it is quick, efficient, and reliable. The weaknesses of gait analysis are that the patients still need to be able to ambulate in some capacity and that it requires specialized, expensive equipment not widely available. Furthermore, temporospatial gait analysis only measures and records footfall placements and does not provide the more comprehensive motion analysis provided by a motion analysis laboratory that includes 3 dimensional kinematic and EMG analysis [27]. This was a pilot study to describe gait and to possibly identify abnormalities in individuals with Pompe by utilizing the simple GAITRite® system, but future studies may use a real 3D gait evaluation in order to gain a more complex perspective on gait of people with Pompe. Other neurological disorders were evaluated by more complex gold standard gait analysis systems, which have greater validity; therefore future in depth studies of gait should make use of these systems [9,28]. Many factors other than muscle strength can affect gait variables including age, gender, height, length of bony components, distribution of mass, joint mobility, and footwear. To limit the impact of these other factors, we compared the data to gender and age matched references and had all subjects walk barefoot. However it is important to note that all of the gait analysis was performed at the end of a physical therapy evaluation which may have biased the results away from the norm. 5. Conclusion The current study is not without limitations, but this study is meant to characterize the temporospatial aspects of gait in individuals with LOPD and to set the stage for further research into the clinical and research-based relevance of this technology. Gait analysis has much potential to add to our understanding LOPD, especially how the natural history may be modified by the use of ERT and other interventions. Gait analysis may be able to: 1) provide early identification of the onset of clinical symptoms through signs in gait; 2) identify specific and pivotal factors which may contribute to functional losses in mobility due to its synergistic and complimentary characteristics in contrast to the 6MWT; 3) offer an additional objective measure of disease status and progression and the impact of intervention; 4) provide a convenient clinical endpoint; 5) help individualize therapeutic exercise programs. Additionally, understanding specific gait patterns in different neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis. By identifying the abnormalities in our population, it will aid in diagnosing individuals with Pompe earlier in neurology clinics, as well as monitoring progressing, and planning treatment. In summary, this study provides the first quantified analysis of gait
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parameters in LOPD, identifying key temporospatial features of gait in LOPD and supporting increasingly comprehensive gait analysis as an important area of future research to expand our understanding of Pompe disease and its successful treatment. Conflict of interest None. Acknowledgments PTM was supported by grant number T35-DK007386 from the National Institutes of Health. LEC has received honoraria from Genzyme Corporation of Sanofi, has participated in research supported by Genzyme Corporation of Sanofi, PTC Therapeutics, the Leal Foundation, Families of SMA, Enobia Pharma Inc./Alexion, the Robertson Foundation, GlaxoSmithKline, Eli Lilly, and CINRG, has been awarded grant support from the National Skeletal Muscle Research Center, and is a member of the Pompe Registry Board of Advisors for Genzyme Corporation of Sanofi. SLA has received honoraria from Genzyme Corporation of Sanofi. PSK has received research/grant support and honoraria from Genzyme Corporation of Sanofi, Amicus Therapeutics, Biomarin Pharmaceutical, Inc., Shire and Advanced Liquid Logic. PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation of Sanofi. The authors thank the individuals with LOPD who participated in the study. References [1] H.G. Hers, alpha-Glucosidase deficiency in generalized glycogenstorage disease (Pompe's disease), Biochem. J. 86 (1963) 11–16. [2] P.S. Kishnani, R.R. Howell, Pompe disease in infants and children, J. Pediatr. 144 (5 Suppl) (2004) S35–S43. [3] S.C. Chiang, et al., Algorithm for Pompe disease newborn screening: results from the Taiwan screening program, Mol. Genet. Metab. 106 (3) (2012) 281–286. [4] L.W. Katzin, A.A. Amato, Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy, J. Clin. Neuromuscul. Dis. 9 (4) (2008) 421–431. [5] L.E. Case, P.S. Kishnani, Physical therapy management of pompe disease, Genitourin. Med. 8 (5) (2006) 318–327. [6] M.L. Hagemans, et al., Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients, Brain 128 (Pt 3) (2005) 671–677. [7] P. Laforet, et al., Juvenile and adult-onset acid maltase deficiency in France: genotypephenotype correlation, Neurology 55 (8) (2000) 1122–1128. [8] A.L. McDonough, et al., The validity and reliability of the GAITRite system's measurements: A preliminary evaluation, Arch. Phys. Med. Rehabil. 82 (3) (2001) 419–425. [9] B. Bilney, M. Morris, K. Webster, Concurrent related validity of the GAITRite walkway system for quantification of the spatial and temporal parameters of gait, Gait Posture 17 (1) (2003) 68–74. [10] A. Gouelle, et al., Validity of Functional Ambulation Performance Score for the evaluation of spatiotemporal parameters of children's gait, J. Mot. Behav. 43 (2) (2011) 95–100. [11] H.G. Chambers, D.H. Sutherland, A practical guide to gait analysis, J. Am. Acad .Orthop. Surg. 10 (3) (2002) 222–231. [12] T. Oberg, A. Karsznia, K. Oberg, Basic gait parameters: reference data for normal subjects, 10–79 years of age, J. Rehabil. Res. Dev. 30 (2) (1993) 210–223. [13] Whittle, M., Gait analysis : an introduction. 3rd ed 2003, Edinburgh; New York: Butterworth-Heinemann. x, 220 p. [14] J.H. Hollman, E.M. McDade, R.C. Petersen, Normative spatiotemporal gait parameters in older adults, Gait Posture 34 (1) (2011) 111–118. [15] M.L. Callisaya, et al., Ageing and gait variability–a population-based study of older people, Age Ageing 39 (2) (2010) 191–197. [16] M.L. Hagemans, et al., Disease severity in children and adults with pompe disease related to age and disease duration, Neurology 64 (12) (2005) 2139–2141. [17] G. Terzis, et al., Effect of aerobic and resistance exercise training on late-onset pompe disease patients receiving enzyme replacement therapy, Mol. Genet. Metab. 104 (3) (2011) 279–283. [18] R. Lachmann, B. Schoser, The clinical relevance of outcomes used in late-onset Pompe disease: can we do better? Orphanet. J. Rare Dis., 8 (2013) 160. [19] C. Angelini, et al., New motor outcome function measures in evaluation of late-onset pompe disease before and after enzyme replacement therapy, Muscle Nerve 45 (6) (2012) 831–834. [20] C.I. van Capelle, et al., The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients, J. Inherit. Metab. Dis. 35 (2) (2012) 317–323. [21] M. Wood, et al., Changes in gait pattern as assessed by the GAITRite walkway system in MPS II patients undergoing enzyme replacement therapy, J. Inherit. Metab. Dis. 32 (Suppl 1) (2009) S127–S135.
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[22] A. Alexander, M.W. Broomfield, N. Finnegan, A. Vellodi, The use of GAITRite® in the evaluation of paediatric patients with Niemann-Pick type C, in 2014 World LSD Meeting, 2014. [23] L.P. Winkel, et al., The natural course of non-classic Pompe's disease; a review of 225 published cases, J. Neurol. 252 (8) (2005) 875–884. [24] Y.H. Chien, W.L. Hwu, N.C. Lee, Pompe disease: early diagnosis and early treatment make a difference, Pediatr. Neonatol. 54 (4) (2013) 219–227. [25] M.G. D'Angelo, et al., Gait pattern in duchenne muscular dystrophy, Gait Posture 29 (1) (2009) 36–41.
[26] S. Armand, et al., A comparison of gait in spinal muscular atrophy, type II and Duchenne muscular dystrophy, Gait Posture 21 (4) (2005) 369–378. [27] M.H. Schwartz, A. Rozumalski, The Gait Deviation Index: a new comprehensive index of gait pathology, Gait Posture 28 (3) (2008) 351–357. [28] K.E. Webster, J.E. Wittwer, J.A. Feller, Validity of the GAITRite walkway system for the measurement of averaged and individual step parameters of gait, Gait Posture 22 (4) (2005) 317–321.
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Characterization of gait in late onset Pompe disease Paul T. McIntosh ⁎, Laura E. Case, Justin M. Chan, Stephanie L. Austin, Priya Kishnani Duke University Medical Center, DUMC 103857, 905 La Salle, GSRB1, 4th Floor Durham, NC 27710
a r t i c l e
i n f o
Article history: Received 1 September 2015 Accepted 1 September 2015 Available online 5 Deptember 2015 Keywords: Pompe disease Neuromuscular disease GAITRite Gait analysis Temporospatial parameters
a b s t r a c t The skeletal muscle manifestations of late-onset Pompe disease (LOPD) cause significant gait impairment. However, the specific temporal and spatial characteristics of abnormal gait in LOPD have not been objectively analyzed or described in the literature. This pilot study evaluated the gait of 22 individuals with LOPD using the GAITRite® temporospatial gait analysis system. The gait parameters were compared to normal reference values, and correlations were made with standard measures of disease progression. The LOPD population demonstrated significant abnormalities in temporospatial parameters of gait including a trend towards decreased velocity and cadence, a prolonged stance phase, prolonged time in double limb support, shorter step and stride length, and a wider base of support. Precise descriptions and analyses of gait abnormalities have much potential in increasing our understanding of LOPD, especially in regards to how its natural history may be modified by the use of enzyme replacement therapy (ERT) and other interventions. Gait analysis may provide a sensitive early marker of the onset of clinical symptoms and signs, offer an additional objective measure of disease progression and the impact of intervention, and serve as a potentially important clinical endpoint. The additional data from comprehensive gait analysis may personalize and optimize physical therapy management, and the clarification of specific gait patterns in neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Pompe disease (Glycogen storage disease type II, GSDII, OMIM # 232300 or acid maltase deficiency) is an autosomal recessive neuromuscular disorder characterized by a deficiency of functional lysosomal enzyme acid α-glucosidase (acid maltase, GAA, OMIM *606,800, EC 3.1.26.2), secondary to mutations in the GAA gene (HGNC:4065) on chromosome 17q25.2-q25.3 [1]. Over time, intra-lysosomal accumulation of glycogen occurs in many tissues, most significantly within skeletal, cardiac, and smooth muscle cells, leading to muscle damage and myopathy [2]. The disease has a broad clinical spectrum ranging from a severe infantile form with generalized hypotonia and hypertrophic cardiomyopathy, to a slowly progressive proximal myopathy with skeletal muscle and respiratory dysfunction in late onset Pompe disease (LOPD) [2]. Newborn screening in Taiwan indicates that the prevalence of the disease may be as high as 1:17,000, although this statistic may disproportionately represent the infantile population since the phenotype is not yet well established [3]. The skeletal muscle weakness in LOPD predominantly manifests proximally with primary involvement of trunk and pelvic girdle
⁎ Corresponding author. E-mail addresses: [email protected], [email protected] (P.T. McIntosh).
http://dx.doi.org/10.1016/j.ymgme.2015.09.001 1096-7192/© 2015 Elsevier Inc. All rights reserved.
musculature with variation in the rate of progression, distribution, and extent of muscle damage [4,5]. The most commonly affected muscle groups in LOPD are the spinal extensors, abdominal muscles, and pelvic girdle muscles [5]. The diaphragm is involved resulting in respiratory compromise and can be selectively involved early in the disease progression. Altogether, the skeletal muscle dysfunction and respiratory problems can lead to dependency on a wheelchair and/or mechanical ventilation. The initial clinical complaints by individuals with LOPD are often related to impaired motor function. Depending on the particular weaknesses and muscle imbalances, individuals may have graded difficulties with activities such as running, climbing stairs, getting out of a chair, and rising from the floor [6]. Patients with LOPD are often caught in a self-perpetuating cycle as the progressive imbalanced muscle weakness, the resulting compensatory movement patterns and postural habits, and the influence of gravity all interact in the progression of motor dysfunction, leading to eventual reliance on mobility assistive devices for ambulation [5]. Ambulation difficulty has been well documented in LOPD, and as much as 87% of the LOPD population experience mobility issues without enzyme replacement therapy (ERT) [6]. However, specific gait characteristics of LOPD are mentioned very little in current literature. The gait in LOPD has simply been described as a waddling gait with a possible presence of lumbar hyperlordosis [7]. To our knowledge, the characteristics of abnormal gait patterns in LOPD have never been
P.T. McIntosh et al. / Molecular Genetics and Metabolism 116 (2015) 152–156
153
quantitatively evaluated. The aim of this study was to collect objective measurements of LOPD patients' gait and to evaluate gait deviations as compared to norms. To this end, we used the GAITRite® (www. gaitrite.com) portable temporospatial gait analysis system to offer initial quantification of gait characteristics of individuals with LOPD.
session by a trained physical therapist. Three of the subjects walked with an assistive device, whereas the other nineteen subjects walked unaided along the mat.
2. Subjects and Methods
The gait cycle is defined as the movement from one foot strike to the subsequent foot strike on the ipsilateral side. It is composed of two primary phases: (i) the stance phase in which the foot is in contact with the ground, and (ii) the swing phase in which the foot is in the air. Bilateral analysis of coordination between these phases considers double limb support versus single limb support [11]. Gait analysis can measure other temporal variables of gait including step time, cadence, and velocity as well as the distance variables of step/stride length and heel-to-heel base of support.
2.1. Subjects The study was performed at Duke University Medical Center in Durham, North Carolina under an IRB approved study; consent was documented for each participant. Inclusion criteria for participation were: 1) confirmation of LOPD with gene mutation analysis and/or enzymatic assay; 2) ability to independently walk at least 10 m with or without the aid of an ambulatory assistance device. Twenty-two individuals with LOPD were included in the study (mean age 48.6 (range 13–72) years). Demographics in Table 1. All of the patients were Caucasian and on ERT at the standard dose of 20 mg/kg every 2 weeks (range 1–10 years; mean 4.2 years) at the time of the study. 2.2. Methods The GAITRite® gait analysis system, consisting of a computer with the GAITRite® software connected to the pressure-sensing GAITRite® electronic portable walking mat, was used for characterization of temporospatial parameters of gait. For the purposes of this study, we focused on gait velocity, cadence, step and stride length, which are directly affected by height, heel-to-heel base of support, and the percentage of time spent in single limb support, double limb support, and swing and stance phases of the gait cycle. The GAITRite® software-generated Functional Ambulation Profile (FAP) is an integrated numerical composite score of gait function, and its reliability has been well documented with values of 0.902–0.970 for test-retest reliability and 0.945–1.000 for inter-rater reliability [8–10]. For each subject in this study, the age, height (cm), body mass (kg), gender, and bilateral lower extremity lengths (cm) were recorded. For each trial, each subject walked barefoot along a mat at a self-selected normal paced speed. These trials were collected after a 2 h clinical
Table 1 Demographics. Study ID Gender Age at GAITRite® Number Assessment (years)
Approximate Time (years) on ERT at GAITRite® Assessment
Use of ambulatory aids
6MWT (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
7 1 1.5 8 7 1.5 5 5 3 1.5 1.5 3 10 2 N/A 2.5 5.5 4 3.5 3.5 7 7
Yes None Yes Yes None Yes Yes None Yes None None None Yes None Yes None Yes None Yes None None Yes
86.63 109.89 90.7 51.16 90.56 74.94 49.97 81.1 92.23 102 58.02 74.23 33.89 96.95 39.4 75.61 64.01 82.46 58.71 53.23 65.92 41.09
F F F F M M F M M M F M M F M F F M M M F M
49 30 72 53 61 55 52 13 66 23 18 50 63 39 60 44 60 52 59 46 61 44
2.3. Gait analysis
2.4. Statistical methods A descriptive statistic was performed for the collected data to determine the distribution and variability in the recorded parameters among the subjects. The data was compared to standardized norms from the literature [12,13]. Normative data for some gait measurements were for ages 20–60; given the age range of this cohort (maximum age 72 years), additional sources for older adults were consulted to ensure appropriate standards for which to compare this cohort [14, 15]. To aid in the comparison of each subject's bilateral (left and right) parameters to the reference ranges, we averaged the left and right values for each parameter and used the resulting single value to determine whether or not the subject fell within or outside of the reference ranges for that parameter. Correlations were made between gait abnormalities and other measures of disease progression using the Pearson product–moment correlation test. 3. Results This study provides descriptive measurements for temporal and spatial parameters of gait compared to normative data, as seen in Table 2. Of note, velocity and cadence were compared to age- and gender-matched healthy reference data. Individual discrepancies from the norm are displayed in Table 3. There was a positive relationship between the FAP score and each individual's performance on the six minute walk test (6MWT) (r = 0.67, p b .05) and on the 10 m fast walk velocity measurement (r = 0.67, p b .05). There was a very strong positive relationship between the performance on the 6MWT and gait velocity (r = 0.79, p b .05) and cadence (r = 0.86, p b .05). Additionally, there was a strong negative relationship between the 6MWT and the percentage of the gait cycle spent in double support (r = −0.70, p b .05). There was not a statistically significant correlation between age and velocity (r = −0.25), cadence (r = −0.24), performance on the 6MWT (r = −0.25) nor the FAP score (r = −0.32), which is consistent with the heterogeneous presentation of LOPD and previous reports that clinical symptoms of LOPD correlate less with age than with disease duration as reflected by time since first symptom onset [16]. 4. Discussion When compared to norms, the LOPD population demonstrated several temporal gait discrepancies secondary to lower extremity and trunk muscle weakness causing decreased stability in single limb support and difficulty during swing. This results in a slower walking speed with increased time in double limb support, the most stable period of the gait cycle. Thus the preferred speed of the LOPD population was slower than that of the references. There were also spatial gait discrepancies in the LOPD population when compared to norms. LOPD exhibited shorter stride length, likely
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Table 2 The averaged gait parameters in the LOPD population compared to reference data.* Parameters
Normal Reference Range [12,13]
Average in LOPD
Percentage of subjects outside the normal range
Standard Error
Standard Deviation
Range
velocity (cm/s) cadence (steps/min) step time (s) cycle time (s) step length (cm) stride length (cm) 2 heel-to-heel base of support (cm) time in single support (%) time in double support (%) time in swing phase (%) time in stance phase (%) FAP score
gender/age specific gender/age specific 0.53–0.59 1.06–1.18 58–85 116–170 5–10 38% - 42% 16% - 24% 36% - 44% 56% - 64% 95–100
101.6 94.7 0.66* 1.31* 63.4 127.5 10.6* 35.7%* 28.7%* 35.7%* 64.3%* 88.7*
64% below reference 95% CI 95% below reference 95% CI 68% below 68% below 32% below 27% below 64% above and 4.5% below 64% below 59% above 32% below 32% above 48% below
6.4 3.5 0.03 0.06 2.6 5.0 0.9 1.1 2.2 1.1 1.1 3.9
30.1 16.5 0.13 0.30 12.2 23.6 4.3 5.1 10.2 5.2 5.2 18.03
112.8 70.3 0.56 1.35 52.6 106.6 19.1 22.3 44.2 23.7 23.6 54
* - indicates outside of norms. Essentially all of the averaged values for the measured parameters in the LOPD population were abnormal except for step and stride length. However, the step length was asymmetrical by more than 4.5 cm in 7 subjects (32%) and 2 subjects (9%) had an asymmetric step length of more than 17 cm. The FAP score, a numerical composite score of gait status, was lower in the LOPD population when compared to normative data indicating decreased gait proficiency.
due to muscle weakness in hip flexors, hip extensors, and ankle plantar flexors. The heel-to-heel base of support tended to be greater in the LOPD population, possibly attributed to the increased stability provided by a wide base of support. One subject has significant mobility impairment, with substantial hip abductor weakness leading to decreased abduction during swing with resultant decreased base of support. The spatial parameters of gait are dependent on height; however the height of the tested population was comparable with a typical US population, except for one 13 year-old patient. In the clinic, gross motor function is evaluated comprehensively with measures of isolated muscle strength, assessment of muscle through timed functional tests and other standardized assessments, and kinematic analysis of individual tasks such as gait. The additional data from comprehensive objective gait analysis may help identify muscles contributing to mobility issues and improve the management of each patient's physical therapy needs. Sub-maximal exercise has been suggested to benefit individuals with LOPD receiving ERT [5,17]. With insight from gait analysis, improved intervention may be possible to preserve optimal body composition, strength, and mobility. Systematic gait analysis is a potential clinical endpoint to use in conjunction with the 6MWT to track disease progression and the
efficacy of therapy. The 6MWT assesses cardiac, pulmonary, circularity, and muscular capacity to provide a measure of functional ability in task performance [18]. It is a useful primary endpoint in the assessment of disease status and patient response to ERT, but additional outcome measures are needed because the current effect of intervention in LOPD is difficult to evaluate due to the heterogeneous phenotype and patterns of response [19]. Gait analysis could aid in the objective evaluation of treatment outcomes, and longitudinal data may serve as a sensitive endpoint that could assess emerging signs and symptoms, disease status, and to detect subtle changes over time [20]. The GAITRite® gait analysis system has been found to be a useful measure of disease progression in Niemann-Pick disease type C and has been investigated as a means to track the effect of ERT in MPS II patients [21,22]. It must be noted that both studies for NPC and MPS II were conducted on pediatric patients, and both MPSII and NPC have additional neurological complications other than muscle weakness than can affect ambulation, such as stiffness, central ataxia, dystonia, and seizures. However, these pediatric studies suggest temporospatial gait analysis could be extended to ambulatory individuals with infantile Pompe disease to monitor disease progression and response to treatment.
Table 3 Gait parameters outside the normal range and performance on several measures of disease progression, with the subjects being ordered by decreasing performance from expected on the six minute walk test (6MWT). Patient number Parameters velocity cadence step time cycle time step length step length differential (N4.5 cm) stride length base of support single support % double support % swing % stance % FAP score 6MWT (% predicted) 10 m fast walk (m/s) GMFM Total (%)
2
10
14
x
x
x
x
9
3
x
x
5
1
x x x x
x x
x x x x x
x
8
16
x x
x x x x
6
12
x x x
x x x
21
x x x x
x
17
x x x x
19
x x x x
11
x x x x
20
x xxx x x x
x x x x x x x x x x x x x x x N/A x 110 102 97 92.2 90.7 90.6 86.8 82.5 81.1 75.6 74.9 74.2 65.9 1.92 2.2 NA 1.92 1.47 1.43 1,79 1.64 1.75 1.32 1.79 1.43 1.05 100 100 N/A N/A N/A N/A 80.5 94.31 N/A 94.31 64.6 94.5 87.41 x
x x x x
18
x x x
4
xxx xxx x x x x
7
22
x x x x x
xxx xxx x x x x
15
xxx xxx x x x x
13
xxx xxx x x x
x x x x x x x x (−) x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 64 58.7 58 53.2 51.2 50 41.1 39.4 33.9 1.11 1.23 1.96 1.16 1.00 1.00 0.91 0.82 0.67 85.04 90.61 98 50.52 N/A N/A N/A 50.98 71.59 x x x
x x x
The data for the 6MWT, the 10 m fast walk velocity, and the GMFM were all collected on the day of the gait assessment. x - indicates a discrepancy from normal; xxx - indicates a substantial discrepancy with regards to velocity and cadence normative value; (−) - indicates an abnormal negative value for base of support.
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Recognizing gait patterns common in LOPD through gait analysis may facilitate timely diagnosis of the disease. The varied and initially nonspecific nature of the early signs and symptoms of this rare disease often results in delayed diagnosis. Additionally, LOPD shares many symptoms with a variety of other neuromuscular disorders, particularly the limb-girdle muscular dystrophies, causing frequent misdiagnosis. These two factors greatly delay accurate diagnosis with the mean delay to diagnosis reported to be 8 to 10 years [23]. Early diagnosis and prompt treatment initiation is critical to slow the progression in this disease, and a discrepancy in ambulatory status could be one of the first signs to present [24]. The presentation of LOPD is quite heterogeneous, but our results suggest that a decreased cadence and velocity are common and can be measured in the clinic without specialized equipment. Further and more comprehensive study of gait characteristics in a larger cohort of LOPD and other neuromuscular diseases would be beneficial in identifying signs suggesting specific diagnostic evaluation. Comprehensive gait analysis has been performed in other neuromuscular disorders including Duchene muscular dystrophy, facioscapulohumeral muscular dystrophy, and spinal muscular atrophy II [25,26]. There are many strengths and weaknesses to utilizing temporospatial gait analysis in the setting of neuromuscular diseases with many implications. The strengths of temporospatial gait analysis are that it is quick, efficient, and reliable. The weaknesses of gait analysis are that the patients still need to be able to ambulate in some capacity and that it requires specialized, expensive equipment not widely available. Furthermore, temporospatial gait analysis only measures and records footfall placements and does not provide the more comprehensive motion analysis provided by a motion analysis laboratory that includes 3 dimensional kinematic and EMG analysis [27]. This was a pilot study to describe gait and to possibly identify abnormalities in individuals with Pompe by utilizing the simple GAITRite® system, but future studies may use a real 3D gait evaluation in order to gain a more complex perspective on gait of people with Pompe. Other neurological disorders were evaluated by more complex gold standard gait analysis systems, which have greater validity; therefore future in depth studies of gait should make use of these systems [9,28]. Many factors other than muscle strength can affect gait variables including age, gender, height, length of bony components, distribution of mass, joint mobility, and footwear. To limit the impact of these other factors, we compared the data to gender and age matched references and had all subjects walk barefoot. However it is important to note that all of the gait analysis was performed at the end of a physical therapy evaluation which may have biased the results away from the norm. 5. Conclusion The current study is not without limitations, but this study is meant to characterize the temporospatial aspects of gait in individuals with LOPD and to set the stage for further research into the clinical and research-based relevance of this technology. Gait analysis has much potential to add to our understanding LOPD, especially how the natural history may be modified by the use of ERT and other interventions. Gait analysis may be able to: 1) provide early identification of the onset of clinical symptoms through signs in gait; 2) identify specific and pivotal factors which may contribute to functional losses in mobility due to its synergistic and complimentary characteristics in contrast to the 6MWT; 3) offer an additional objective measure of disease status and progression and the impact of intervention; 4) provide a convenient clinical endpoint; 5) help individualize therapeutic exercise programs. Additionally, understanding specific gait patterns in different neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis. By identifying the abnormalities in our population, it will aid in diagnosing individuals with Pompe earlier in neurology clinics, as well as monitoring progressing, and planning treatment. In summary, this study provides the first quantified analysis of gait
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parameters in LOPD, identifying key temporospatial features of gait in LOPD and supporting increasingly comprehensive gait analysis as an important area of future research to expand our understanding of Pompe disease and its successful treatment. Conflict of interest None. Acknowledgments PTM was supported by grant number T35-DK007386 from the National Institutes of Health. LEC has received honoraria from Genzyme Corporation of Sanofi, has participated in research supported by Genzyme Corporation of Sanofi, PTC Therapeutics, the Leal Foundation, Families of SMA, Enobia Pharma Inc./Alexion, the Robertson Foundation, GlaxoSmithKline, Eli Lilly, and CINRG, has been awarded grant support from the National Skeletal Muscle Research Center, and is a member of the Pompe Registry Board of Advisors for Genzyme Corporation of Sanofi. SLA has received honoraria from Genzyme Corporation of Sanofi. PSK has received research/grant support and honoraria from Genzyme Corporation of Sanofi, Amicus Therapeutics, Biomarin Pharmaceutical, Inc., Shire and Advanced Liquid Logic. PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation of Sanofi. The authors thank the individuals with LOPD who participated in the study. References [1] H.G. Hers, alpha-Glucosidase deficiency in generalized glycogenstorage disease (Pompe's disease), Biochem. J. 86 (1963) 11–16. [2] P.S. Kishnani, R.R. Howell, Pompe disease in infants and children, J. Pediatr. 144 (5 Suppl) (2004) S35–S43. [3] S.C. Chiang, et al., Algorithm for Pompe disease newborn screening: results from the Taiwan screening program, Mol. Genet. Metab. 106 (3) (2012) 281–286. [4] L.W. Katzin, A.A. Amato, Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy, J. Clin. Neuromuscul. Dis. 9 (4) (2008) 421–431. [5] L.E. Case, P.S. Kishnani, Physical therapy management of pompe disease, Genitourin. Med. 8 (5) (2006) 318–327. [6] M.L. Hagemans, et al., Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients, Brain 128 (Pt 3) (2005) 671–677. [7] P. Laforet, et al., Juvenile and adult-onset acid maltase deficiency in France: genotypephenotype correlation, Neurology 55 (8) (2000) 1122–1128. [8] A.L. McDonough, et al., The validity and reliability of the GAITRite system's measurements: A preliminary evaluation, Arch. Phys. Med. Rehabil. 82 (3) (2001) 419–425. [9] B. Bilney, M. Morris, K. Webster, Concurrent related validity of the GAITRite walkway system for quantification of the spatial and temporal parameters of gait, Gait Posture 17 (1) (2003) 68–74. [10] A. Gouelle, et al., Validity of Functional Ambulation Performance Score for the evaluation of spatiotemporal parameters of children's gait, J. Mot. Behav. 43 (2) (2011) 95–100. [11] H.G. Chambers, D.H. Sutherland, A practical guide to gait analysis, J. Am. Acad .Orthop. Surg. 10 (3) (2002) 222–231. [12] T. Oberg, A. Karsznia, K. Oberg, Basic gait parameters: reference data for normal subjects, 10–79 years of age, J. Rehabil. Res. Dev. 30 (2) (1993) 210–223. [13] Whittle, M., Gait analysis : an introduction. 3rd ed 2003, Edinburgh; New York: Butterworth-Heinemann. x, 220 p. [14] J.H. Hollman, E.M. McDade, R.C. Petersen, Normative spatiotemporal gait parameters in older adults, Gait Posture 34 (1) (2011) 111–118. [15] M.L. Callisaya, et al., Ageing and gait variability–a population-based study of older people, Age Ageing 39 (2) (2010) 191–197. [16] M.L. Hagemans, et al., Disease severity in children and adults with pompe disease related to age and disease duration, Neurology 64 (12) (2005) 2139–2141. [17] G. Terzis, et al., Effect of aerobic and resistance exercise training on late-onset pompe disease patients receiving enzyme replacement therapy, Mol. Genet. Metab. 104 (3) (2011) 279–283. [18] R. Lachmann, B. Schoser, The clinical relevance of outcomes used in late-onset Pompe disease: can we do better? Orphanet. J. Rare Dis., 8 (2013) 160. [19] C. Angelini, et al., New motor outcome function measures in evaluation of late-onset pompe disease before and after enzyme replacement therapy, Muscle Nerve 45 (6) (2012) 831–834. [20] C.I. van Capelle, et al., The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients, J. Inherit. Metab. Dis. 35 (2) (2012) 317–323. [21] M. Wood, et al., Changes in gait pattern as assessed by the GAITRite walkway system in MPS II patients undergoing enzyme replacement therapy, J. Inherit. Metab. Dis. 32 (Suppl 1) (2009) S127–S135.
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