Extensive mobile health technology assessment detects subtle motor impairment in mild and asymptomatic Pompe disease

Extensive mobile health technology assessment detects subtle motor impairment in mild and asymptomatic Pompe disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Extensive mobile health technology assessment detects subtle motor impairment in mild and asymptomatic Pompe disease Andrea Pilotto, Beatrice Labella, Andrea Rizzardi, Cinzia Zatti, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4529770/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract The aim of the study was to evaluate the ability of mobile health technology (MHT) to detect and quantify mobility alterations in late-onset Pompe Disease (PD). The study enrolled eight subjects with PD, including three young mildly affected/asymptomatic subjects, who underwent an extensive MHT mobility assessment and were contrasted to matched controls. MHT assessment enabled the detection of subtle mobility alterations, indicating a lower speed in walking, postural transition and turning lower performances in PD subjects compared to controls. Interestingly, in the three mildly affected/asymptomatic cases, clinical scales and timed tests scored within the normal ranges, whereas gait digital parameters showed detectable subtle alterations compared to controls. Health sciences/Biomarkers/Prognostic markers Health sciences/Neurology/Neurological disorders Biological sciences/Neuroscience Health sciences/Biomarkers Health sciences/Neurology Pompe disease digital technology mobile health technology mobility progression INTRODUCTION Pompe disease (PD) is an autosomal recessive disorder caused by a deficiency of the acid alpha-glucosidase (GAA) enzyme, whose function is to hydrolyze glycogen to glucose in the lysosome 1 , 2 . PD has been classified according to age at onset into severe infantile form and late-onset form (LOPD) which presents a more heterogeneous involvement of respiratory and skeletal muscles 2 – 4 . Since 2006, the use of the recombinant enzyme alglucosidase alfa (Myozyme®/Lumizyme®) has demonstrated its efficacy in stabilizing motor and pulmonary function, leading to a life-changing scenario for both infantile and adult patients 3 , 5 . However, among LOPD patients, a high level of variability in their responses to the treatment was observed, and many subjects experienced some degree of secondary decline after 3–5 years 6 . During the last decade, this led to several studies aimed at expanding the therapeutic options to include novel rhGAAs (avalglucosidase alfa), chaperone-enhanced rhGAA (cipaglucosidase), and even gene therapy 7 , 8 . One of the main issues in managing LOPD patients is the best way to assess the response to treatment because the sensitivity of the current clinical scales and timed tests does not seem optimal, especially in evaluating mild forms 2 , 9 . Recent studies have supported the use of mobile health technologies (MHT) to assess subtle mobility changes in response to interventions in different clinical conditions 10 – 12 . In this study we applied a comprehensive MHT assessment of gait, turning, and postural transition to detect subtle mobility changes in LOPD patients and investigate a subgroup of mildly affected or asymptomatic LOPD subjects with the aim of defining its usefulness as a outcome measure in evaluating disease burden and progression and, possibly, therapeutic efficacy compared to standard clinical assessment. PATIENTS AND METHODS Clinical assessment This prospective study included patients with a genetic diagnosis of LOPD followed at the ERN-Euro NMD Center for Neuromuscular Diseases in Brescia, Italy (Unit of Neurology and NeMO-Brescia Clinical Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia) under enzyme-replacement treatment (ERT) with alglucosidase alpha. Neurologically healthy controls were recruited from patients’ families and from healthy volunteers and were matched for age with the patients. The following inclusion criteria were applied for both groups: i) ability to walk without aids ii) lack of medical conditions or medication with potential impact on gait and mobility. The research protocol was approved by the Ethics Committee of the Brescia Hospital, Brescia, Italy (DMA study, NP 1471). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all participants. Each LOPD patient underwent an extensive clinical protocol including several clinical scales used in clinical trials and observational studies. Functional endurance was assessed by the 6-minute walking test (6MWT), which measures aerobic capacity by the distance (meters) walked in 6 minutes and is a well-known secondary outcome measure in clinical trials for PD 7 . The motor performances in daily life were evaluated by the Gardner-Medwin-Walton (WGM) scale, Timed Up and Go (TUG) test, and Gait, Stairs, Gower, Chair score (GCSG) scale 9 . WGM scale is a validated score ranging from 0 to 10, with 0 indicating the normal conditions and 10 the inability to conduct any activity. GSGC scale has recently been introduced and investigate the performances in four motor tasks (Gait by walking for 10 meters, climbing 4 steps on a stair, Gower’s manoeuvre, rising from a Chair), ranging from 4 (normal performance) to 27 (worst performance in non-ambulatory patients). The daily life impact of the disease was assessed by Rasch-Built Pompe-specific Activity scale (R-Pact), Pompe Disease Symptom Scale (PDSS) and Pompe Disease Impact Scale (PDIS). These scales are simple self-report questionnaires based on daily or social activities that may be affected by the disease. The R-Pact consists of 18 items in order of increasing difficulty and the score for each item is defined as 0 = unable to perform, 1 = able to perform with difficulty, 2 = able to perform without difficulty 13 . The PDSS is based on 12 items with specific focus on fatigue, in which patients rate the severity of symptoms in the last 24 hours from 0 to 10 14 . Nevertheless, the 15-item PDIS questionnaire provides a picture of mood and mobility-related activities over the previous 24 hours 9 , 14 . Mobile Health technology assessment The RehaGait® system consists of three mobile inertial sensors (dimensions: 60 × 15 × 35 mm); each sensor comprises a 3-axis accelerometer (± 16 g), a 3- axis gyroscope (± 2000 °/s) and a 3-triaxial magnetometer (± 1.3 125 Gs). The sensors were attached to the lateral side of each shoe using special straps and at the level of the fifth lumbar spine segment close to the centre of mass to measure linear acceleration, angular velocity and the magnetic field at a sampling rate of 100 Hz 15 . Raw data were processed using Matlab R2022b (MathWorks, Natick, MA, USA). To analyse gait parameters the raw data of the IMU from the lower back was used. As stated in the method session, only variables with a percentage of missing data lower than 5% were considered. Outliers were defined by a value higher or lower than 3 standard deviation of the disease-specific group and were excluded from the analyses. As described in the references, the raw accelerometer and gyroscope data were processed to first detect the gait events 16 , 17 . Step time was defined as the time between two consecutive heel strikes, step time variabilities were calculated extracting standard deviation (SD) from all steps 18 . Step length was calculated as previously reported by Welzel and coauthors 19 . 6MWT-Fatigability was specifically evaluated by contrasting steps- 4-104 with the last 100 steps detected during the 6minute walking test. Asymmetry was defined as the average absolute difference between left and right steps for each walking pass. The parameters included in the final analyses were duration of TUG, duration of turns, peak and mean angular velocities (in degrees per second), for the whole turning. Mean values from the clockwise and counterclockwise turns were used 20 , 21 . Postural transition digital assessment included PT duration, speed and angular velocity based on vertical displacement of the IMU placed on the low bac 16 , 22 . Statistical analysis Differences in demographic and clinical parameters between participants with LOPD and controls were not normally distributed and non-parametric test adjusted for age and sex were used for all analyses. For the secondary analyses focused on mildly affected/asymptomatic cases, a younger group of controls (n = 21, age 27 ± 1.9) was selected. All analyses were 2-tailed, and p < 0.05 was considered as statistically significant. RESULTS Eight LOPD patients (mean age 43 years, Female 3/8, 37%), five symptomatic and three mildly affected/asymptomatic and 52 matched controls (mean age 44 years, female 38%) entered the study (Table 1 ). The five symptomatic patients presented heterogeneous motor impairment, as scored by clinical scales and 6MWT. Out of the three mildly affected/asymptomatic patients, only one was diagnosed because of mild fatigability during adolescence, while the other two were asymptomatic at diagnosis (incidental finding of hyperCKemia, diagnosis in first grade relative). Asymptomatic patients at diagnosis later started ERT due to magnetic resonance imaging of muscle fatty substitution. At the clinical scale and timed test, all mildly affected/asymptomatic subjects scored within the normal range except one patient with borderline GSGC score. Differences in digital parameters have been summarized in Tables 2 – 4 . Table 1 Clinical characteristics of LOPD included in the study. *indicates values considered abnormal at individual levels according to the cut-off of specific scales and test (see references for specific cut offs of validated scale). Abbreviations: GSGC, Gower, Chair score; R-PACT, Rasch-Built Pompe-specific Activity scale; PDIS, Pompe disease Impact scale; PDSS, Pompe disease symptom scale; TUG, timed up and go test; WGM, Gardner-Medwin-Walton scale; 6MWT, 6-minute walking test PT Onset symptoms Age at diagnosis Genetic diagnosis Age at start ERT Age at assessment R-PACT Scale PDSS PDIS WGM Scale GSGC score TUG right foot (sec) 6MWT (m) 3 Mildly symptomatic (mild Fatigue) 16 c.-32-13T > G; c.2237G > A Splice; Nonsense 17 19 33 2 1 0 4 7 530 2 Asymptomatic 18 c.[2481_2646del]; c.-32-13T > G Deletion; Splice 20 21 35 6 2 0 4 9 470 1 Asymptomatic 2 c.32-13T > G; c.1670T > G Splice; Missense 23 28 34 3 0 0 5 * 10 420 7 Motor impairment 35 y.o. 36 c.-32-13T > G; c.-32-13T > G Splice; Frameshift 37 48 35 12 2 2 * 5 * 7 555 5 Motor impairment 28 y.o. 29 c.-32-13T > G; c.2481 + 102_2646 + 31del Splice; Large deletion 44 50 16 57 45 3 * 16 * 21 * 300 * 8 Motor impairment 40 y.o. 41 c.-32-13T > G; c.2237G > A Splice; Nonsense 41 53 18 71 53 3 * 15 * 17 * 281 * 4 Motor impairment 36 y.o. 37 c.-32-13T > G; c.2237G > A Splice; Nonsense 47 63 29 43 35 2 * 9 * 14 * 405 * 6 Motor impairment 53 y.o. 54 c.-32-13T > G; c.1927G > A Splice; Missense 55 64 25 28 24 2 * 10 * 15 * 420 In the walking task, LOPD patients exhibited a lower number of steps with a longer step time, shorter step length and increased step time variability, compared to controls (Supplementary Fig. 1, Table 2 ). The comparison between the first and last 100 walking bouts showed similar trends in Pompe and controls during the 6MWT task (Table 3 ). In the turning task, LOPD patients exhibited lower angular and peak velocities, and a slightly higher turning duration, than controls. In the postural transition task during TUG, LOPD patients showed a longer duration of standing. Moreover, in the Five Times sit-to-stand Test, they showed lower extension maximal velocity during the standing up phases and a longer duration of the standing phases between the transitions (Supplementary Fig. 1, Table 4 ). Clinical scores correlated significantly with peak angular velocity of turning, sit to stand duration of the Five Times sit-to-stand Test and number of steps of the 6MWT (Supplementary Fig. 1). Table 2 Mobile health technology assessment evaluating walking and turning in LOPD compared to matched control subjects. The assessment evaluated gait and turning parameters. Abbreviations: TUG, timed up and go test. Parameter LOPD patients (n = 8) Healthy controls (n = 52) P-value Walking normal speed Step counts (n) 578 (± 136.34) 710 (± 56.59) 0.02 Step time (s) 0.67 (± 0.28) 0.51 (± 0.38) < 0.001 Step time variability (s) 0.07 (± 0.03) 0.04 (± 0.01) < 0.001 Step asymmetry 0.02 (± 0.01) 0.01 (± 0.10) 0.27 Step Length 0.61 (± 0.14) 0.69 (± 0.07) 0.05 Turning during TUG Angle of turns (grades) 179.52 (± 16.02) 183.25 (± 26.10) 0.58 Duration turning (sec) 2.33 (± 0.58) 2.22 (± 0.58) 0.17 Angular velocity (rad/s) 79.83 (± 20.31) 90.76 (± 16.55) 0.02 Peak angular velocity (rad/s) 176.79 (± 43.23) 213.25 (± 36.62) 0.01 Table 3 Variation of walking parameters in LOPD compared to age matched control subjects (%) between the first and last steps (4-104 vs last 100 steps detected) during the 6MWT. Parameter LOPD patients (n = 8) Healthy controls (n = 52) P-value Step time + 3.12 + 1.90 0.425 Stance time + 3.44 + 1.91 0.180 Double Limb Support + 3.10 + 2.21 0.358 Step Time Variability + 2.90 + 1.35 0.201 Asymmetry + 3.20 + 1.47 0.159 Table 4 Postural transition parameters in LOPD compared to control subjects (Means (± standard deviations)). The task has been assessed one single time and repeated 5 times separately- according to the short physical performance battery protocol. Parameter LOPD patients (n = 8) Healthy controls (n = 52) P-value Single Task sit to stand (during TUG) Sit to Stand Duration (sec) 3.13 (± 0.87) 2.01 (± 0.42) < 0.001 Angle (grades) 50.45 (± 15.77) 43.45 (± 10.71) 0.069 Extension max velocity (cm/s) 75.76 (± 16.42) 83.87 (± 21.84) 0.415 Flexion max velocity (cm/s) 119.73 (± 51.58) 149.51 (± 45.31) 0.091 Repeated 5-chair stand Stand to Sit duration (sec) 2.23 (± 1.08) 1.42 (± 0.38) < 0.001 Angle Stand To Sit (grades) 44.40 (± 18.48) 37.4 (± 11.6) 0.20 Extension max velocity (cm/s) 70.38 (± 21.87) 94,35 (± 35.56) 0.05 Flexion max velocity (cm/s) 95.21 (± 29.60) 104.72 (± 34.10) 0.06 Mildly affected/asymptomatic LOPD subjects exhibited higher step time variability and lower step length, compared to age-matched controls, whereas no significant differences in the number of steps and step time were detected (Table 5 ). In turning and sit-to-stand tasks, a trend towards reduced peak and normal angular speed and longer task duration was observed (Supplementary Tables 1 and 2). Table 5 Walking parameters in asymptomatic LOPD (aLOPD) patients compared to younger matched controls. Abbreviations : TUG, timed up and go test. Parameter aLOPD patients (n = 3) Healthy controls (n = 21) P-value Walking normal speed Step counts (n) 640.33 (± 27.4) 708.23 (± 56.59) 0.121 Step time (s) 0.56 (± 0.02) 0.51 (± 0.04) 0.101 Step time variability (s) 0.06 (± 0.03) 0.03 (± 0.01) 0.001 Step asimmetry 0.01 (± 0.01) 0.01 (± 0.01) 0.737 Step Length 0.54 (± 0.13) 0.68 (± 0.06) 0.001 DISCUSSION LOPD is a debilitating, progressive disorder that imposes significant challenges on affected individuals and their families 23 , 24 . Characterized by insidious onset and gradual progression, LOPD primarily affects the skeletal and respiratory muscles, leading to increased morbidity and decreased quality of life 23 , 24 . In this context, the development and implementation of robust outcome measures is essential for accurately tracking disease progression, evaluating therapeutic efficacy, and ultimately improving patient care and outcomes. One of the foremost needs of LOPD outcome measures is their sensitivity to detect subtle changes over time. LOPD progresses slowly, and often the incremental decline in muscle strength or respiratory function can be missed by less sensitive measures 25 , 26 . Tools that can capture these minute changes are useful for early intervention and for assessing the true impact of therapeutic strategies. Without such sensitivity, we risk underestimating the disease's progression and overestimating the efficacy of interventions. To date, outcome measures used in Pompe Disease, as derived from clinical trials, include functional tests such as the 6-minute walk test (6MWT) and the timed up-and-go (TUG) test, alongside assessments of activities of daily living (ADLs), respiratory function assessments (forced vital capacity), and patient-reported outcomes (PROs) able to detect patients' perceptions of their own health, symptoms, and the impact of the disease on daily life 7 , 27 – 30 . As new therapies emerge, outcome measures must evolve to capture their specific impacts. This adaptability ensures that the measures remain relevant and continue to provide meaningful data that reflects the benefits or limitations of novel treatments. Digital parameters obtained by MHT have recently demonstrated their validity as outcome measures in several conditions, including movement disorders and Duchenne muscular dystrophy 10 – 13 . In LOPD, only one preliminary study has been conducted in this area using FitBit OneTM data to track the number of steps taken by moderately and severely affected patients 14 . The study showed a reduction in total step count in LOPD, with a reasonable correlation with disease severity and disease duration. To our best knowledge, ours is the first study to use a comprehensive MHT assessment in LOPD to study motor changes. The results of this small pilot study may be relevant for the research community, which is still searching for reliable outcome measures 2 , 6 , 14 , 25 , 26 . It shows a wide range of mobility changes in fully symptomatic and mildly affected/asymptomatic subjects. Considering the total number of LOPD subjects, significant changes in the walking task (lower number of steps, longer step time, shorter step length, and increased step time variability), turning task (lower angular and peak velocities, and slightly higher turning duration), and postural transition task (longer duration of standing) were observed compared to controls. A significant correlation with clinical scores was found for peak angular velocity of turning, sit-to-stand duration of the Five Times sit-to-stand Test, and number of steps of the 6MWT. Interestingly, our study went further to evaluate mildly affected or asymptomatic LOPD patients in a supervised setting, focusing on a wider range of components, namely walking, turning, and postural changes. Gait analysis in this subgroup of subjects showed reduced step length and increased variability, despite normal scores on clinical scales and timed motor tests. Overall, the variability of walking parameters in LOPD was slightly increased but substantially like the control group between the first and last 100 steps. This may suggest that the differences in walking parameters are related to a stable deficit undetectable by routine scores rather than fatigability. Turning and postural transition tasks also revealed subtle changes that could be related to axial muscle weakness, even though they did not reach statistical significance in this subgroup. Of course, the small number of subjects remains the main limitation of this study, although we have demonstrated the validity of MHT assessment even with a limited sample size and high heterogeneity of motor involvement. Our findings need to be confirmed in larger ongoing longitudinal studies and extended to unsupervised settings, which are known to be more effective and sensitive to detect multiple symptoms in different conditions, as demonstrated in Parkinson's disease, multiple sclerosis, and even healthy aging 17 , 31 . Notwithstanding this limitation, our preliminary results suggest that wearable technologies can identify subtle walking abnormalities also in mildly affected or asymptomatic patients not otherwise evident by usual clinical evaluation. They may have important implications for management, follow-up, and treatment decisions in clinical practice. Importantly, our results suggest that MHT deserve to be evaluated as a promising outcome measure for clinical trials. Declarations Acknowledgments We thank the participants in this study for their time and willingness to contribute this research. Andrea Pilotto, Beatrice Labella, Andrea Rizzardi, Chiara Trasciatti, Filomena Caria, Barbara Risi, Simona Damioli, Emanuele Olivieri, Lucia Ferullo, Loris Poli, Alessandro Padovani and Massimiliano Filosto are part of the ERN Euro NMD, HCP ASST Spedali Civili, Brescia, Italy. Funding The study was partially financially supported for the assessment of controls by the Airalzh Foundation AGYR2021 Life-Bio Grant, The LIMPE-DISMOV Foundation Segala Grant 2021, the H2020 IMI IDEA-FAST (ID853981), Italian Ministry of Health, Grant/Award Number: RF-2018-12366209 and PNRR-Health PNRR-MAD-2022-12376110. Author contribution A.Pi., B.L., A.R., C.Z., W.M., A.Pa. and M.F. contributed to the conception and design of the study; A.Pi, B.L., A.R., C.Z., C.H., R.R., S.C.P, W.M and A.Pa. contributed to the acquisition and analyses of data; A.Pi., B.L., A.R.,C.Z.,C.H., R.R., W.M., A.Pa and M.F contributed to drafting the text; A.Pi., I.L., C.Z., C.H. and R.R contributed to statistical analyses. All authors read and approved the final manuscript. Consent statement The Ethics Committee approved the Brescia Hospital's research protocol (NP 3710). Written informed consent was obtained from all participants. Methods and Data Availability The raw data supporting the conclusions of this article will be made available by the corresponding author, without undue reservation. Competing interest Andrea Pilotto received grant support from Airalzh Foundation AGYR2021 Life-Bio Grant, The LIMPE-DISMOV Foundation Segala Grant 2021, the Italian Ministry of University and Research PRIN COCOON (2017MYJ5TH) and PRIN 2021 RePlast, the H2020 IMI IDEA-FAST (ID853981), Italian Ministry of Health, Grant/Award Number: RF-2018-12366209 and PNRR-Health PNRR-MAD-2022-12376110 Beatrice Labella, Andrea Rizzardi, Cinzia Zatti, Chiara Trasciatti, Stefano Cotti Piccinelli, Filomena Caria, Barbara Risi, Simona Damioli, Emanuele Olivieri, Lucia Ferullo, Loris Poli report no conflict of interest. Clint Hansen, Robbin Romijnders, Johanna Geritz report no conflict of interest. Walter Maetzler receives or received funding from the European Union, the German Federal Ministry of Education of Research, German Research Council, Michael J. Fox Foundation, Neuroalliance, Lundbeck, Sivantos and Janssen. He received speaker honoraria from Abbvie, Bayer, BIAL, GlaxoSmithKline, Heel, Licher MT, Rölke Pharma, Takeda and UCB, was invited to Advisory Boards / Consultancies of Abbvie, Aptar Digital Health, Atheneum, Biogen, Kyowa Kirin, Lundbeck and Pfizer, is an advisory board member of the Critical Path for Parkinson's Consortium and the MDS e-Diary Working Group, and an editorial board member of Geriatric Care. He is a member of the MDS Technology Working Group. Alessandro Padovani received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), IMI H2020 initiative (IMI2-2018-15-06). Massimiliano Filosto received grant support from Telethon Italy Foundation and Italian Ministry of University and Research PRIN PNRR 2022. The other authors declare no competing interests. References Lim, J.A., Li, L., Raben, N. Pompe disease: from pathophysiology to therapy and back again. Front Aging Neurosci . 6 :177 (2014). doi: 10.3389/fnagi.2014.00177. Labella, B. et al . A Comprehensive Update on Late-Onset Pompe Disease. Biomolecules . 13 (9):1279 (2023). doi: 10.3390/biom13091279. Kishnani, P.S. et al . Recombinant human acid α-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology . 68 (2):99-109 (2007). doi: 10.1212/01.wnl.0000251268.41188.04. Erratum in: Neurology . 71 (21):1748 (2008). Angelini, C., Engel, A.G. Comparative study of acid maltase deficiency. Biochemical differences between infantile, childhood, and adult types. Arch Neurol . 26 (4):344-9 (1972). doi: 10.1001/archneur.1972.00490100074007. Kuperus, E. et al . 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Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial. JAMA Neurol. 2023 Jun 1;80(6):558-567. doi: 10.1001/jamaneurol.2023.0552. Toscano, A. et al . Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial. Mol Genet Metab. 2024 Feb;141(2):108121. doi: 10.1016/j.ymgme.2023.108121. Warmerdam, E. et al . Long-term unsupervised mobility assessment in movement disorders. Lancet Neurol. 2020 May;19(5):462-470. doi: 10.1016/S1474-4422(19)30397-7. Additional Declarations Competing interest reported. Andrea Pilotto received grant support from Airalzh Foundation AGYR2021 Life-Bio Grant, The LIMPE-DISMOV Foundation Segala Grant 2021, the Italian Ministry of University and Research PRIN COCOON (2017MYJ5TH) and PRIN 2021 RePlast, the H2020 IMI IDEA-FAST (ID853981), Italian Ministry of Health, Grant/Award Number: RF-2018-12366209 and PNRR-Health PNRR-MAD-2022-12376110.Walter Maetzler receives or received funding from the European Union, the German Federal Ministry of Education of Research, German Research Council, Michael J. Fox Foundation, Neuroalliance, Lundbeck, Sivantos and Janssen. He received speaker honoraria from Abbvie, Bayer, BIAL, GlaxoSmithKline, Heel, Licher MT, Rölke Pharma, Takeda and UCB, was invited to Advisory Boards / Consultancies of Abbvie, Aptar Digital Health, Atheneum, Biogen, Kyowa Kirin, Lundbeck and Pfizer, is an advisory board member of the Critical Path for Parkinson's Consortium and the MDS e-Diary Working Group, and an editorial board member of Geriatric Care. He is a member of the MDS Technology Working Group. Alessandro Padovani received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), IMI H2020 initiative (IMI2-2018-15-06). Massimiliano Filosto received grant support from Telethon Italy Foundation and Italian Ministry of University and Research PRIN PNRR 2022. The other authors declare no competing interests. Supplementary Files SupplementaryMaterial.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 11 Nov, 2024 Reviews received at journal 20 Oct, 2024 Reviewers agreed at journal 28 Sep, 2024 Reviews received at journal 21 Jul, 2024 Reviewers agreed at journal 21 Jul, 2024 Reviewers agreed at journal 18 Jul, 2024 Reviewers invited by journal 17 Jul, 2024 Editor assigned by journal 17 Jul, 2024 Editor invited by journal 23 Jun, 2024 Submission checks completed at journal 18 Jun, 2024 First submitted to journal 04 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Brescia","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Padovani","suffix":""},{"id":321783727,"identity":"db004338-34e8-4657-8e40-8e7b16b4762f","order_by":17,"name":"Massimiliano Filosto","email":"","orcid":"","institution":"University of Brescia","correspondingAuthor":false,"prefix":"","firstName":"Massimiliano","middleName":"","lastName":"Filosto","suffix":""}],"badges":[],"createdAt":"2024-06-04 18:00:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4529770/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4529770/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59577822,"identity":"74f3c851-95be-49ee-a56c-f735f63bc450","added_by":"auto","created_at":"2024-07-03 11:42:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":696443,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4529770/v1/d1d196e1-88c8-49bb-b24b-263ba83ca1b6.pdf"},{"id":59577068,"identity":"8d40f85a-a762-4aaf-a184-148f4c233286","added_by":"auto","created_at":"2024-07-03 11:34:07","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":186004,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4529770/v1/e2987813309ebc2479566778.pdf"}],"financialInterests":"Competing interest reported. Andrea Pilotto received grant support from Airalzh Foundation AGYR2021 Life-Bio Grant, The LIMPE-DISMOV Foundation Segala Grant 2021, the Italian Ministry of University and Research PRIN COCOON (2017MYJ5TH) and PRIN 2021 RePlast, the H2020 IMI IDEA-FAST (ID853981), Italian Ministry of Health, Grant/Award Number: RF-2018-12366209 and PNRR-Health PNRR-MAD-2022-12376110.Walter Maetzler receives or received funding from the European Union, the German Federal Ministry of Education of Research, German Research Council, Michael J. Fox Foundation, Neuroalliance, Lundbeck, Sivantos and Janssen. He received speaker honoraria from Abbvie, Bayer, BIAL, GlaxoSmithKline, Heel, Licher MT, Rölke Pharma, Takeda and UCB, was invited to Advisory Boards / Consultancies of Abbvie, Aptar Digital Health, Atheneum, Biogen, Kyowa Kirin, Lundbeck and Pfizer, is an advisory board member of the Critical Path for Parkinson's Consortium and the MDS e-Diary Working Group, and an editorial board member of Geriatric Care. He is a member of the MDS Technology Working Group.\nAlessandro Padovani received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), IMI H2020 initiative (IMI2-2018-15-06).\nMassimiliano Filosto received grant support from Telethon Italy Foundation and Italian Ministry of University and Research PRIN PNRR 2022.\nThe other authors declare no competing interests.","formattedTitle":"Extensive mobile health technology assessment detects subtle motor impairment in mild and asymptomatic Pompe disease","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePompe disease (PD) is an autosomal recessive disorder caused by a deficiency of the acid alpha-glucosidase (GAA) enzyme, whose function is to hydrolyze glycogen to glucose in the lysosome\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePD has been classified according to age at onset into severe infantile form and late-onset form (LOPD) which presents a more heterogeneous involvement of respiratory and skeletal muscles\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Since 2006, the use of the recombinant enzyme alglucosidase alfa (Myozyme\u0026reg;/Lumizyme\u0026reg;) has demonstrated its efficacy in stabilizing motor and pulmonary function, leading to a life-changing scenario for both infantile and adult patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, among LOPD patients, a high level of variability in their responses to the treatment was observed, and many subjects experienced some degree of secondary decline after 3\u0026ndash;5 years\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. During the last decade, this led to several studies aimed at expanding the therapeutic options to include novel rhGAAs (avalglucosidase alfa), chaperone-enhanced rhGAA (cipaglucosidase), and even gene therapy\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOne of the main issues in managing LOPD patients is the best way to assess the response to treatment because the sensitivity of the current clinical scales and timed tests does not seem optimal, especially in evaluating mild forms\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRecent studies have supported the use of mobile health technologies (MHT) to assess subtle mobility changes in response to interventions in different clinical conditions\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study we applied a comprehensive MHT assessment of gait, turning, and postural transition to detect subtle mobility changes in LOPD patients and investigate a subgroup of mildly affected or asymptomatic LOPD subjects with the aim of defining its usefulness as a outcome measure in evaluating disease burden and progression and, possibly, therapeutic efficacy compared to standard clinical assessment.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical assessment\u003c/h2\u003e \u003cp\u003e This prospective study included patients with a genetic diagnosis of LOPD followed at the ERN-Euro NMD Center for Neuromuscular Diseases in Brescia, Italy (Unit of Neurology and NeMO-Brescia Clinical Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia) under enzyme-replacement treatment (ERT) with alglucosidase alpha.\u003c/p\u003e \u003cp\u003eNeurologically healthy controls were recruited from patients\u0026rsquo; families and from healthy volunteers and were matched for age with the patients. The following inclusion criteria were applied for both groups: i) ability to walk without aids ii) lack of medical conditions or medication with potential impact on gait and mobility.\u003c/p\u003e \u003cp\u003e The research protocol was approved by the Ethics Committee of the Brescia Hospital, Brescia, Italy (DMA study, NP 1471). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all participants.\u003c/p\u003e \u003cp\u003eEach LOPD patient underwent an extensive clinical protocol including several clinical scales used in clinical trials and observational studies. Functional endurance was assessed by the 6-minute walking test (6MWT), which measures aerobic capacity by the distance (meters) walked in 6 minutes and is a well-known secondary outcome measure in clinical trials for PD\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The motor performances in daily life were evaluated by the Gardner-Medwin-Walton (WGM) scale, Timed Up and Go (TUG) test, and Gait, Stairs, Gower, Chair score (GCSG) scale\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. WGM scale is a validated score ranging from 0 to 10, with 0 indicating the normal conditions and 10 the inability to conduct any activity. GSGC scale has recently been introduced and investigate the performances in four motor tasks (Gait by walking for 10 meters, climbing 4 steps on a stair, Gower\u0026rsquo;s manoeuvre, rising from a Chair), ranging from 4 (normal performance) to 27 (worst performance in non-ambulatory patients).\u003c/p\u003e \u003cp\u003eThe daily life impact of the disease was assessed by Rasch-Built Pompe-specific Activity scale (R-Pact), Pompe Disease Symptom Scale (PDSS) and Pompe Disease Impact Scale (PDIS). These scales are simple self-report questionnaires based on daily or social activities that may be affected by the disease. The R-Pact consists of 18 items in order of increasing difficulty and the score for each item is defined as 0\u0026thinsp;=\u0026thinsp;unable to perform, 1\u0026thinsp;=\u0026thinsp;able to perform with difficulty, 2\u0026thinsp;=\u0026thinsp;able to perform without difficulty\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The PDSS is based on 12 items with specific focus on fatigue, in which patients rate the severity of symptoms in the last 24 hours from 0 to 10\u003csup\u003e14\u003c/sup\u003e. Nevertheless, the 15-item PDIS questionnaire provides a picture of mood and mobility-related activities over the previous 24 hours\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMobile Health technology assessment\u003c/h2\u003e \u003cp\u003eThe RehaGait\u0026reg; system consists of three mobile inertial sensors (dimensions: 60 \u0026times; 15 \u0026times; 35 mm); each sensor comprises a 3-axis accelerometer (\u0026plusmn;\u0026thinsp;16 g), a 3- axis gyroscope (\u0026plusmn;\u0026thinsp;2000 \u0026deg;/s) and a 3-triaxial magnetometer (\u0026plusmn;\u0026thinsp;1.3 125 Gs). The sensors were attached to the lateral side of each shoe using special straps and at the level of the fifth lumbar spine segment close to the centre of mass to measure linear acceleration, angular velocity and the magnetic field at a sampling rate of 100 Hz\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRaw data were processed using Matlab R2022b (MathWorks, Natick, MA, USA). To analyse gait parameters the raw data of the IMU from the lower back was used. As stated in the method session, only variables with a percentage of missing data lower than 5% were considered. Outliers were defined by a value higher or lower than 3 standard deviation of the disease-specific group and were excluded from the analyses. As described in the references, the raw accelerometer and gyroscope data were processed to first detect the gait events\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Step time was defined as the time between two consecutive heel strikes, step time variabilities were calculated extracting standard deviation (SD) from all steps\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Step length was calculated as previously reported by Welzel and coauthors\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e6MWT-Fatigability was specifically evaluated by contrasting steps- 4-104 with the last 100 steps detected during the 6minute walking test. Asymmetry was defined as the average absolute difference between left and right steps for each walking pass. The parameters included in the final analyses were duration of TUG, duration of turns, peak and mean angular velocities (in degrees per second), for the whole turning. Mean values from the clockwise and counterclockwise turns were used\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Postural transition digital assessment included PT duration, speed and angular velocity based on vertical displacement of the IMU placed on the low bac\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDifferences in demographic and clinical parameters between participants with LOPD and controls were not normally distributed and non-parametric test adjusted for age and sex were used for all analyses. For the secondary analyses focused on mildly affected/asymptomatic cases, a younger group of controls (n\u0026thinsp;=\u0026thinsp;21, age 27\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.9) was selected. All analyses were 2-tailed, and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eEight LOPD patients (mean age 43 years, Female 3/8, 37%), five symptomatic and three mildly affected/asymptomatic and 52 matched controls (mean age 44 years, female 38%) entered the study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe five symptomatic patients presented heterogeneous motor impairment, as scored by clinical scales and 6MWT. Out of the three mildly affected/asymptomatic patients, only one was diagnosed because of mild fatigability during adolescence, while the other two were asymptomatic at diagnosis (incidental finding of hyperCKemia, diagnosis in first grade relative). Asymptomatic patients at diagnosis later started ERT due to magnetic resonance imaging of muscle fatty substitution. At the clinical scale and timed test, all mildly affected/asymptomatic subjects scored within the normal range except one patient with borderline GSGC score. Differences in digital parameters have been summarized in Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of LOPD included in the study. *indicates values considered abnormal at individual levels according to the cut-off of specific scales and test (see references for specific cut offs of validated scale). Abbreviations: GSGC, Gower, Chair score; R-PACT, Rasch-Built Pompe-specific Activity scale; PDIS, Pompe disease Impact scale; PDSS, Pompe disease symptom scale; TUG, timed up and go test; WGM, Gardner-Medwin-Walton scale; 6MWT, 6-minute walking test\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOnset symptoms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge at diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGenetic diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAge at\u003c/p\u003e \u003cp\u003estart ERT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003eat assessment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eR-PACT\u003c/p\u003e \u003cp\u003eScale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePDSS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePDIS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eWGM Scale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eGSGC\u003c/p\u003e \u003cp\u003escore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eTUG right foot\u003c/p\u003e \u003cp\u003e(sec)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003e6MWT\u003c/p\u003e \u003cp\u003e(m)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMildly symptomatic\u003c/p\u003e \u003cp\u003e(mild Fatigue)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.2237G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e530\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsymptomatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.[2481_2646del];\u003c/p\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDeletion;\u003c/p\u003e \u003cp\u003eSplice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e470\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsymptomatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.1670T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e5 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e420\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMotor impairment\u003c/p\u003e \u003cp\u003e35 y.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e5 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e555\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMotor impairment\u003c/p\u003e \u003cp\u003e28 y.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.2481\u0026thinsp;+\u0026thinsp;102_2646\u003c/p\u003e \u003cp\u003e+\u0026thinsp;31del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eLarge deletion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e16 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e21 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e300 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMotor impairment\u003c/p\u003e \u003cp\u003e40 y.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.2237G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e15 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e17 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e281 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMotor impairment\u003c/p\u003e \u003cp\u003e36 y.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.2237G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e9 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e14 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e405 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMotor impairment\u003c/p\u003e \u003cp\u003e53 y.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G;\u003c/p\u003e \u003cp\u003ec.1927G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSplice;\u003c/p\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e10 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e15 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e420\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the walking task, LOPD patients exhibited a lower number of steps with a longer step time, shorter step length and increased step time variability, compared to controls (Supplementary Fig.\u0026nbsp;1, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The comparison between the first and last 100 walking bouts showed similar trends in Pompe and controls during the 6MWT task (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the turning task, LOPD patients exhibited lower angular and peak velocities, and a slightly higher turning duration, than controls. In the postural transition task during TUG, LOPD patients showed a longer duration of standing. Moreover, in the Five Times sit-to-stand Test, they showed lower extension maximal velocity during the standing up phases and a longer duration of the standing phases between the transitions (Supplementary Fig.\u0026nbsp;1, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Clinical scores correlated significantly with peak angular velocity of turning, sit to stand duration of the Five Times sit-to-stand Test and number of steps of the 6MWT (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMobile health technology assessment evaluating walking and turning in LOPD compared to matched control subjects. The assessment evaluated gait and turning parameters. Abbreviations: TUG, timed up and go test.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLOPD patients (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthy controls (n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eWalking normal speed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep counts (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e578 (\u0026plusmn;\u0026thinsp;136.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e710 (\u0026plusmn;\u0026thinsp;56.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep time\u0026nbsp;(s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67 (\u0026plusmn;\u0026thinsp;0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51 (\u0026plusmn;\u0026thinsp;0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep time variability (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.07 (\u0026plusmn;\u0026thinsp;0.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.04 (\u0026plusmn;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep asymmetry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.02 (\u0026plusmn;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.01 (\u0026plusmn;\u0026thinsp;0.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep Length\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.61 (\u0026plusmn;\u0026thinsp;0.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.69 (\u0026plusmn;\u0026thinsp;0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eTurning during TUG\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAngle of turns (grades)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179.52 (\u0026plusmn;\u0026thinsp;16.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183.25 (\u0026plusmn;\u0026thinsp;26.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration turning (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.33 (\u0026plusmn;\u0026thinsp;0.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.22 (\u0026plusmn;\u0026thinsp;0.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAngular velocity (rad/s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79.83 (\u0026plusmn;\u0026thinsp;20.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90.76 (\u0026plusmn;\u0026thinsp;16.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak angular velocity (rad/s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176.79 (\u0026plusmn;\u0026thinsp;43.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e213.25 (\u0026plusmn;\u0026thinsp;36.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eVariation of walking parameters in LOPD compared to age matched control subjects (%) between the first and last steps (4-104 vs last 100 steps detected) during the 6MWT.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLOPD patients (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthy controls (n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;1.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.425\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStance time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;3.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDouble Limb Support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;3.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;2.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep Time Variability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;2.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsymmetry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;3.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;1.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.159\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostural transition parameters in LOPD compared to control subjects (Means (\u0026plusmn;\u0026thinsp;standard deviations)). The task has been assessed one single time and repeated 5 times separately- according to the short physical performance battery protocol.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLOPD patients (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthy controls (n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSingle Task sit to stand (during TUG)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSit to Stand Duration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.13 (\u0026plusmn;\u0026thinsp;0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.01 (\u0026plusmn;\u0026thinsp;0.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAngle (grades)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.45 (\u0026plusmn;\u0026thinsp;15.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.45 (\u0026plusmn;\u0026thinsp;10.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtension max velocity (cm/s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.76 (\u0026plusmn;\u0026thinsp;16.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.87 (\u0026plusmn;\u0026thinsp;21.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.415\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFlexion max velocity (cm/s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119.73 (\u0026plusmn;\u0026thinsp;51.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e149.51 (\u0026plusmn;\u0026thinsp;45.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRepeated 5-chair stand\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStand to Sit duration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.23 (\u0026plusmn;\u0026thinsp;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.42 (\u0026plusmn;\u0026thinsp;0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAngle Stand To Sit (grades)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.40 (\u0026plusmn;\u0026thinsp;18.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.4 (\u0026plusmn;\u0026thinsp;11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtension max velocity (cm/s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.38 (\u0026plusmn;\u0026thinsp;21.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94,35 (\u0026plusmn;\u0026thinsp;35.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFlexion max velocity (cm/s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95.21 (\u0026plusmn;\u0026thinsp;29.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104.72 (\u0026plusmn;\u0026thinsp;34.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMildly affected/asymptomatic LOPD subjects exhibited higher step time variability and lower step length, compared to age-matched controls, whereas no significant differences in the number of steps and step time were detected (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). In turning and sit-to-stand tasks, a trend towards reduced peak and normal angular speed and longer task duration was observed (Supplementary Tables\u0026nbsp;1 and 2).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eWalking parameters in asymptomatic LOPD (aLOPD) patients compared to younger matched controls. \u003cb\u003eAbbreviations\u003c/b\u003e: TUG, timed up and go test.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaLOPD patients (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthy controls (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eWalking normal speed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep counts (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e640.33 (\u0026plusmn;\u0026thinsp;27.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e708.23 (\u0026plusmn;\u0026thinsp;56.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep time\u0026nbsp;(s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.56 (\u0026plusmn;\u0026thinsp;0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.51 (\u0026plusmn;\u0026thinsp;0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep time variability (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.06 (\u0026plusmn;\u0026thinsp;0.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.03 (\u0026plusmn;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep asimmetry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.01 (\u0026plusmn;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.01 (\u0026plusmn;\u0026thinsp;0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.737\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep Length\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.54 (\u0026plusmn;\u0026thinsp;0.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.68 (\u0026plusmn;\u0026thinsp;0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eLOPD is a debilitating, progressive disorder that imposes significant challenges on affected individuals and their families\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Characterized by insidious onset and gradual progression, LOPD primarily affects the skeletal and respiratory muscles, leading to increased morbidity and decreased quality of life\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In this context, the development and implementation of robust outcome measures is essential for accurately tracking disease progression, evaluating therapeutic efficacy, and ultimately improving patient care and outcomes.\u003c/p\u003e \u003cp\u003eOne of the foremost needs of LOPD outcome measures is their sensitivity to detect subtle changes over time. LOPD progresses slowly, and often the incremental decline in muscle strength or respiratory function can be missed by less sensitive measures\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Tools that can capture these minute changes are useful for early intervention and for assessing the true impact of therapeutic strategies. Without such sensitivity, we risk underestimating the disease's progression and overestimating the efficacy of interventions.\u003c/p\u003e \u003cp\u003eTo date, outcome measures used in Pompe Disease, as derived from clinical trials, include functional tests such as the 6-minute walk test (6MWT) and the timed up-and-go (TUG) test, alongside assessments of activities of daily living (ADLs), respiratory function assessments (forced vital capacity), and patient-reported outcomes (PROs) able to detect patients' perceptions of their own health, symptoms, and the impact of the disease on daily life\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs new therapies emerge, outcome measures must evolve to capture their specific impacts. This adaptability ensures that the measures remain relevant and continue to provide meaningful data that reflects the benefits or limitations of novel treatments.\u003c/p\u003e \u003cp\u003eDigital parameters obtained by MHT have recently demonstrated their validity as outcome measures in several conditions, including movement disorders and Duchenne muscular dystrophy\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn LOPD, only one preliminary study has been conducted in this area using FitBit OneTM data to track the number of steps taken by moderately and severely affected patients\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The study showed a reduction in total step count in LOPD, with a reasonable correlation with disease severity and disease duration.\u003c/p\u003e \u003cp\u003eTo our best knowledge, ours is the first study to use a comprehensive MHT assessment in LOPD to study motor changes. The results of this small pilot study may be relevant for the research community, which is still searching for reliable outcome measures\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. It shows a wide range of mobility changes in fully symptomatic and mildly affected/asymptomatic subjects.\u003c/p\u003e \u003cp\u003eConsidering the total number of LOPD subjects, significant changes in the walking task (lower number of steps, longer step time, shorter step length, and increased step time variability), turning task (lower angular and peak velocities, and slightly higher turning duration), and postural transition task (longer duration of standing) were observed compared to controls. A significant correlation with clinical scores was found for peak angular velocity of turning, sit-to-stand duration of the Five Times sit-to-stand Test, and number of steps of the 6MWT.\u003c/p\u003e \u003cp\u003eInterestingly, our study went further to evaluate mildly affected or asymptomatic LOPD patients in a supervised setting, focusing on a wider range of components, namely walking, turning, and postural changes. Gait analysis in this subgroup of subjects showed reduced step length and increased variability, despite normal scores on clinical scales and timed motor tests. Overall, the variability of walking parameters in LOPD was slightly increased but substantially like the control group between the first and last 100 steps. This may suggest that the differences in walking parameters are related to a stable deficit undetectable by routine scores rather than fatigability. Turning and postural transition tasks also revealed subtle changes that could be related to axial muscle weakness, even though they did not reach statistical significance in this subgroup.\u003c/p\u003e \u003cp\u003eOf course, the small number of subjects remains the main limitation of this study, although we have demonstrated the validity of MHT assessment even with a limited sample size and high heterogeneity of motor involvement. Our findings need to be confirmed in larger ongoing longitudinal studies and extended to unsupervised settings, which are known to be more effective and sensitive to detect multiple symptoms in different conditions, as demonstrated in Parkinson's disease, multiple sclerosis, and even healthy aging\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNotwithstanding this limitation, our preliminary results suggest that wearable technologies can identify subtle walking abnormalities also in mildly affected or asymptomatic patients not otherwise evident by usual clinical evaluation. They may have important implications for management, follow-up, and treatment decisions in clinical practice. Importantly, our results suggest that MHT deserve to be evaluated as a promising outcome measure for clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the participants in this study for their time and willingness to contribute this research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAndrea Pilotto, Beatrice Labella, Andrea Rizzardi, Chiara Trasciatti, Filomena Caria, Barbara Risi, Simona Damioli, Emanuele Olivieri, Lucia Ferullo, Loris Poli, Alessandro Padovani and Massimiliano Filosto are part of the ERN Euro NMD, HCP ASST Spedali Civili, Brescia, Italy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was partially financially supported for the assessment of controls by the Airalzh Foundation AGYR2021 Life-Bio Grant, The LIMPE-DISMOV Foundation Segala Grant 2021, the H2020 IMI IDEA-FAST \u0026nbsp;(ID853981), Italian Ministry of Health, Grant/Award Number: RF-2018-12366209 and PNRR-Health PNRR-MAD-2022-12376110.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.Pi., B.L., A.R., C.Z., W.M., A.Pa. and M.F. contributed to the conception and design of the study; A.Pi, B.L., A.R., C.Z., C.H., R.R., S.C.P, W.M and A.Pa. contributed to the acquisition and analyses of data; A.Pi., B.L., A.R.,C.Z.,C.H., R.R., W.M., A.Pa and M.F contributed to drafting the text; A.Pi., I.L., C.Z., C.H. and R.R contributed to statistical analyses. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee approved the Brescia Hospital's research protocol (NP 3710). Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and Data Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the corresponding author, without undue reservation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAndrea Pilotto received grant support from Airalzh Foundation AGYR2021 Life-Bio Grant, The LIMPE-DISMOV Foundation Segala Grant 2021, the Italian Ministry of University and Research PRIN COCOON (2017MYJ5TH) and PRIN 2021 RePlast, the H2020 IMI IDEA-FAST \u0026nbsp; (ID853981), Italian Ministry of Health, Grant/Award Number: RF-2018-12366209 and PNRR-Health PNRR-MAD-2022-12376110\u003c/p\u003e\n\u003cp\u003eBeatrice Labella, Andrea Rizzardi, Cinzia Zatti, Chiara Trasciatti, Stefano Cotti Piccinelli, Filomena Caria, Barbara Risi, Simona Damioli, Emanuele Olivieri, Lucia Ferullo, Loris Poli report no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClint Hansen, Robbin Romijnders, Johanna Geritz\u0026nbsp;report no conflict of\u0026nbsp;interest. Walter Maetzler receives or received funding from the European Union, the German Federal Ministry of Education of Research, German Research Council, Michael J. Fox Foundation, Neuroalliance, Lundbeck, Sivantos and Janssen. He received speaker honoraria from Abbvie, Bayer, BIAL, GlaxoSmithKline, Heel, Licher MT, Rölke Pharma, Takeda and UCB, was invited to Advisory Boards / Consultancies of Abbvie, Aptar Digital Health, Atheneum, Biogen, Kyowa Kirin, Lundbeck and Pfizer, is an advisory board member of the Critical Path for Parkinson's Consortium and the MDS e-Diary Working Group, and an editorial board member of Geriatric Care. He is a member of the MDS Technology Working Group.\u003c/p\u003e\n\u003cp\u003eAlessandro Padovani received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), IMI H2020 initiative (IMI2-2018-15-06).\u003c/p\u003e\n\u003cp\u003eMassimiliano Filosto received grant support from Telethon Italy Foundation and Italian Ministry of University and Research PRIN PNRR 2022.\u003c/p\u003e\n\u003cp\u003eThe other authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLim, J.A., Li, L., Raben, N. Pompe disease: from pathophysiology to therapy and back again. \u003cem\u003eFront Aging Neurosci\u003c/em\u003e. \u003cstrong\u003e6\u003c/strong\u003e:177 (2014). doi: 10.3389/fnagi.2014.00177.\u003c/li\u003e\n\u003cli\u003eLabella, B. \u003cem\u003eet al\u003c/em\u003e. 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Motor, cognitive and mobility deficits in 1000 geriatric patients: protocol of a quantitative observational study before and after routine clinical geriatric treatment - the ComOn-study. BMC Geriatr. 2020 Feb 6;20(1):45. doi: 10.1186/s12877-020-1445-z. \u003c/li\u003e\n\u003cli\u003ePham, M. \u003cem\u003eet al\u003c/em\u003e. Validation of a step detection algorithm during straight walking and turning in patients with Parkinson\u0026rsquo;s disease and older adults using an inertial measurement unit at the lower back. \u003cem\u003eFront. Neurol\u003c/em\u003e. \u003cstrong\u003e8\u003c/strong\u003e:457 (2017). doi: 10.3389/fneur.2017.00457\u003c/li\u003e\n\u003cli\u003ePilotto, A. \u003cem\u003eet al\u003c/em\u003e. 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Postural transitions detection and characterization in healthy and patient populations using a single waist sensor. \u003cem\u003eJ Neuroeng Rehabil\u003c/em\u003e. \u003cstrong\u003e17\u003c/strong\u003e(1):70 (2020). doi: 10.1186/s12984-020-00692-4. \u003c/li\u003e\n\u003cli\u003eSchoser, B. \u003cem\u003eet al\u003c/em\u003e. The humanistic burden of Pompe disease: are there still unmet needs? A systematic review. BMC Neurol. 2017 Nov 22;17(1):202. doi: 10.1186/s12883-017-0983-2. \u003c/li\u003e\n\u003cli\u003eHagemans, M.L. \u003cem\u003eet al\u003c/em\u003e. Late-onset Pompe disease primarily affects quality of life in physical health domains. Neurology. 2004 Nov 9;63(9):1688-92. doi: 10.1212/01.wnl.0000142597.69707.78. \u003c/li\u003e\n\u003cli\u003eLachmann, R., Schoser, B. The clinical relevance of outcomes used in late-onset Pompe disease: can we do better? 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Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial. JAMA Neurol. 2023 Jun 1;80(6):558-567. doi: 10.1001/jamaneurol.2023.0552. \u003c/li\u003e\n\u003cli\u003eToscano, A. \u003cem\u003eet al\u003c/em\u003e. Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-na\u0026iuml;ve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial. Mol Genet Metab. 2024 Feb;141(2):108121. doi: 10.1016/j.ymgme.2023.108121. \u003c/li\u003e\n\u003cli\u003eWarmerdam, E. \u003cem\u003eet al\u003c/em\u003e. Long-term unsupervised mobility assessment in movement disorders. Lancet Neurol. 2020 May;19(5):462-470. doi: 10.1016/S1474-4422(19)30397-7. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pompe disease, digital technology, mobile health technology, mobility, progression","lastPublishedDoi":"10.21203/rs.3.rs-4529770/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4529770/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aim of the study was to evaluate the ability of mobile health technology (MHT) to detect and quantify mobility alterations in late-onset Pompe Disease (PD). The study enrolled eight subjects with PD, including three young mildly affected/asymptomatic subjects, who underwent an extensive MHT mobility assessment and were contrasted to matched controls. MHT assessment enabled the detection of subtle mobility alterations, indicating a lower speed in walking, postural transition and turning lower performances in PD subjects compared to controls. Interestingly, in the three mildly affected/asymptomatic cases, clinical scales and timed tests scored within the normal ranges, whereas gait digital parameters showed detectable subtle alterations compared to controls.\u003c/p\u003e","manuscriptTitle":"Extensive mobile health technology assessment detects subtle motor impairment in mild and asymptomatic Pompe disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-03 11:34:02","doi":"10.21203/rs.3.rs-4529770/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-11T09:51:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-20T18:00:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"150604100008676918366705040063916383967","date":"2024-09-28T15:39:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-21T07:59:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291154919865354813632707739616364181225","date":"2024-07-21T07:23:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"113972685087645733290557553626514246484","date":"2024-07-18T08:51:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-17T21:13:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-17T21:10:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-23T14:09:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-18T04:42:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-04T17:59:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2bf315a3-ae73-4034-9d21-1ba4cbc6e258","owner":[],"postedDate":"July 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":34021020,"name":"Health sciences/Biomarkers/Prognostic markers"},{"id":34021021,"name":"Health sciences/Neurology/Neurological disorders"},{"id":34021022,"name":"Biological sciences/Neuroscience"},{"id":34021023,"name":"Health sciences/Biomarkers"},{"id":34021024,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2025-08-05T05:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-03 11:34:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4529770","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4529770","identity":"rs-4529770","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}