Publications by authors named "Louise A M Otto"

12 Publications

  • Page 1 of 1

Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study.

Orphanet J Rare Dis 2022 02 21;17(1):70. Epub 2022 Feb 21.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Respiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life.

Methods: We measured maximal expiratory and inspiratory pressure (PE and PI), Sniff Nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and peak cough flow (PCF) in treatment-naïve patients with SMA. We used mixed-models to analyze natural history patterns.

Results: We included 2172 measurements of respiratory muscle function from 80 treatment-naïve patients with SMA types 1c-3b. All outcomes were lower in the more severe phenotypes. Significant differences in PEF were present between SMA types from early ages onwards. PEF decline was linear (1-2%/year). PEF reached values below 80% during early childhood in types 1c-2, and during adolescence in type 3a. PE and PI were severely lowered in most patients throughout life, with PE values abnormally low (i.e. < 80 cmHO) in virtually all patients. The PE/PI ratio was < 1 throughout life in all SMA types, indicating that expiratory muscles were most affected. All but SMA type 3b patients had a lowered PCF. Patients with types 2b and 3a had PCF levels between 160 and 270 L/min, those with type 2a around 160 L/min and patients with type 1c well below 160 L/min. Finally, SNIP was low in nearly all patients, most pronounced in more severely affected patients.

Conclusions: There are clear differences in respiratory muscle strength and its progressive decline between SMA types. We observed lower outcomes in more severe SMA types. Particularly PEF may be a suitable outcome measure for the follow-up of respiratory strength in patients with SMA. PEF declines in a rather linear pattern in all SMA types, with clear differences at baseline. These natural history data may serve as a reference for longer-term treatment efficacy assessments.
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http://dx.doi.org/10.1186/s13023-022-02227-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862532PMC
February 2022

Quantification of disease progression in spinal muscular atrophy with muscle MRI-a pilot study.

NMR Biomed 2021 04 22;34(4):e4473. Epub 2021 Jan 22.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Objectives: Quantitative MRI (qMRI) of muscles is a promising tool to measure disease progression or to assess therapeutic effects in neuromuscular diseases. Longitudinal imaging studies are needed to show sensitivity of qMRI in detecting disease progression in spinal muscular atrophy (SMA). In this pilot study we therefore studied one-year changes in quantitative MR parameters in relation to clinical scores.

Methods: We repeated quantitative 3 T MR analysis of thigh muscles and clinical testing one year after baseline in 10 treatment-naïve patients with SMA, 5 with Type 2 (21.6 ± 7.0 years) and 5 with Type 3 (33.4 ± 11.9 years). MR protocol consisted of Dixon, T mapping and diffusion tensor imaging (DTI). The temporal relation of parameters was examined with a mixed model.

Results: We detected a significant increase in fat fraction (baseline, 38.2% SE 0.6; follow-up, 39.5% SE 0.6; +1.3%, p = 0.001) in all muscles. Muscles with moderate to high fat infiltration at baseline show a larger increase over time (+1.6%, p < 0.001). We did not find any changes in DTI parameters except for low fat-infiltration muscles (m. adductor longus and m. biceps femoris (short head)). The T of muscles decreased from 28.2 ms to 28.0 ms (p = 0.07). Muscle strength and motor function scores were not significantly different between follow-up and baseline.

Conclusion: Longitudinal imaging data show slow disease progression in skeletal muscle of the thigh of (young-) adult patients with SMA despite stable strength and motor function scores. Quantitative muscle imaging demonstrates potential as a biomarker for disease activity and monitoring of therapy response.
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http://dx.doi.org/10.1002/nbm.4473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988555PMC
April 2021

Muscle strength and motor function in adolescents and adults with spinal muscular atrophy.

Neurology 2020 10 30;95(14):e1988-e1998. Epub 2020 Jul 30.

From the Department of Neurology (C.A.W., M.S., L.A.M.O., F.-L.A., R.P.A.v.E., L.H.v.d.B., H.S.G., R.I.W., W.L.v.d.P.), UMC Utrecht Brain Center, Child Development and Exercise Center (B.B.), and Department of Biostatistics & Research Support (R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To assess longitudinal patterns of muscle strength, motor function, and maximal compound muscle action potential amplitudes (CMAP) in older patients with spinal muscular atrophy (SMA), hypothesizing a continued decline of motor function parameters throughout life.

Methods: We measured muscle strength (Medical Research Council), motor function (Hammersmith Functional Motor Scale Expanded [HFMSE] and Motor Function Measure), and CMAP in treatment-naive patients. We used both longitudinal and cross-sectional data in mixed models to analyze natural history patterns.

Results: We included 250 patients with SMA types 1c through 4. Median patient age at assessment was 26.8 years, the number of assessments per patient ranged from 1 to 6. Baseline muscle strength and motor function scores differed significantly between SMA types, but annual rates of decline were largely similar and mostly linear. HFMSE floor effects were present for all patients with SMA type 1c, and adolescents and adults with types 2 and 3a. CMAP differed significantly between SMA types but did not decline significantly with increasing age. Muscle strength correlated very strongly with motor function (τ ≥ 0.8) but only moderately with CMAP (τ ≈ 0.5-0.6).

Conclusion: Muscle strength and motor function decline in older patients with SMA are constant without periods of slower progression or a plateau phase. The floor effects of the HFMSE preclude its use for long-term follow-up of adult patients with SMA types 1c through 3a. Muscle strength sum scores represent an alternative, feasible outcome measure for adolescent and adult patients with SMA.
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http://dx.doi.org/10.1212/WNL.0000000000010540DOI Listing
October 2020

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

NMR Biomed 2020 10 18;33(10):e4357. Epub 2020 Jul 18.

Department of Radiology, University Medical Center Utrecht, Utrecht University, the Netherlands.

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.6-73.9] years) and 20 healthy controls (aged 37.9 [17.7-71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = -0.56 and -0.59; both P < .001) whereas for fat fraction values are τ = -0.50 and -0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.
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http://dx.doi.org/10.1002/nbm.4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507182PMC
October 2020

T relaxation-time mapping in healthy and diseased skeletal muscle using extended phase graph algorithms.

Magn Reson Med 2020 11 19;84(5):2656-2670. Epub 2020 Apr 19.

Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Purpose: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T of the myocytic component (T ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T .

Methods: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T calibration methods and T estimations.

Results: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T up to 10 ms. Furthermore, a wrongly calibrated T caused a bias of up to 4 ms in T . For the in vivo data, one-component calibration led to a lower T compared with a two-component method, and T decreased with increasing fat fractions.

Conclusion: In vivo data showed a decline in T for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T from MSE sequences with two-component T calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements.
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http://dx.doi.org/10.1002/mrm.28290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496817PMC
November 2020

Assessment of motor unit loss in patients with spinal muscular atrophy.

Clin Neurophysiol 2020 06 13;131(6):1280-1286. Epub 2020 Feb 13.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans.

Methods: We performed CMAP scan recordings in median nerves of 24 treatment-naïve patients (median age 39; range 12-75 years) with SMA types 2-4. From each scan, we determined maximum CMAP amplitude (CMAP), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans.

Results: Median CMAP was 8.1 mV (range 0.9-14.6 mV), MUNE was 29 (range 6-131), and D50 was 25 (range 2-57). We found a reduced D50 (<25) in patients with normal CMAP (n = 12), indicating MU loss and enlarged MUs due to reinnervation. Lower D50 values were associated with decreased MUNE (P < 0.001, r = 0.68, n = 43). CMAP, MUNE and D50 values differed between SMA types (P < 0.001). Lower motor function scores were related to patients with lower CMAP, MUNE and D50 values (P < 0.001).

Conclusions: The CMAP scan is an easily applicable technique that is superior to routine assessment of CMAP in SMA.

Significance: The detection of pathological MU changes across the spectrum of SMA may provide important biomarkers for evaluating disease course and monitoring treatment efficacy.
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http://dx.doi.org/10.1016/j.clinph.2020.01.018DOI Listing
June 2020

Natural history of lung function in spinal muscular atrophy.

Orphanet J Rare Dis 2020 04 10;15(1):88. Epub 2020 Apr 10.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3508, GA, Utrecht, The Netherlands.

Background: Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail.

Results: We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from - 0.1% to - 1.4% for FEV, - 0.2% to - 1.4% for FVC, and + 0.2% to - 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV values measured in either sitting or supine position.

Conclusions: Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.
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http://dx.doi.org/10.1186/s13023-020-01367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149916PMC
April 2020

Population-based analysis of survival in spinal muscular atrophy.

Neurology 2020 04 26;94(15):e1634-e1644. Epub 2020 Mar 26.

From the Department of Neurology, UMC Utrecht Brain Center (C.A.W., M.S., L.A.M.O., R.P.A.v.E., I.C., L.H.v.d.B., R.I.W., W.L.v.d.P.), Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.v.E.), and Department of Pediatric Intensive Care (E.S.V.), University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To investigate probabilities of survival and its surrogate, that is, mechanical ventilation, in patients with spinal muscular atrophy (SMA).

Methods: We studied survival in a population-based cohort on clinical prevalence of genetically confirmed, treatment-naive patients with SMA, stratified for best acquired motor milestone (i.e., none: type 1a/b; head control in supine position or rolling: type 1c; sitting independently: type 2a; standing: type 2b; walking: type 3a/b; adult onset: type 4). We also assessed the need for mechanical ventilation as a surrogate endpoint for survival.

Results: We included 307 patients with a total follow-up of 7,141 person-years. Median survival was 9 days in SMA type 1a, 7.7 months in type 1b, and 17.0 years in type 1c. Patients with type 2a had endpoint-free survival probabilities of 74.2% and 61.5% at ages 40 and 60 years, respectively. Endpoint-free survival of SMA types 2b, 3, and 4 was relatively normal, at least within the first 60 years of life. Patients with SMA types 1c and 2a required mechanical ventilation more frequently and from younger ages compared to patients with milder SMA types. In our cohort, patients ventilated up to 12 h/d progressed not gradually, but abruptly, to ≥16 h/d.

Conclusions: Shortened endpoint-free survival is an important characteristic of SMA types 1 and 2a, but not types 2b, 3, and 4. For SMA types 1c and 2a, the age at which initiation of mechanical ventilation is necessary may be a more suitable endpoint than the arbitrarily set 16 h/d.
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http://dx.doi.org/10.1212/WNL.0000000000009248DOI Listing
April 2020

Magnetic resonance imaging of the cervical spinal cord in spinal muscular atrophy.

Neuroimage Clin 2019 3;24:102002. Epub 2019 Sep 3.

UMC Utrecht Brain Center, Department of Neurology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. Electronic address:

Objective: In this study we investigated the potential value of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in characterizing changes in the cervical spinal cord and peripheral nerve roots in vivo in patients with spinal muscular atrophy (SMA).

Methods: We developed an MRI protocol with 4 sequences to investigate the cervical spinal cord and nerve roots on a 3 Tesla MRI system. We used 2 anatomical MRI sequences to investigate cross-sectional area (CSA) at each spinal segment and the diameter of ventral and dorsal nerve roots, and two diffusion tensor imaging (DTI) techniques to estimate the fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD) in 10 SMA patients and 20 healthy controls.

Results: There were no significant differences in CSA (p > .1), although an 8.5% reduction of CSA in patients compared to healthy controls was apparent at segment C7. DTI data showed a higher AD in grey matter of patients compared to healthy controls (p = .033). Significantly lower MD, AD and RD values were found in rostral nerve roots (C3-C5) in patients (p < .045).

Conclusions: We showed feasibility of an advanced 3 T MRI protocol that allowed differences to be determined between patients and healthy controls, confirming the potential of this technique to assess pathological mechanisms in SMA. After further development and confirmation of findings in a larger sample, these techniques may be used to study disease course of SMA in vivo and evaluate response to survival motor neuron (SMN) augmenting therapy.
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http://dx.doi.org/10.1016/j.nicl.2019.102002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812296PMC
September 2020

Multi-center evaluation of stability and reproducibility of quantitative MRI measures in healthy calf muscles.

NMR Biomed 2019 09 17;32(9):e4119. Epub 2019 Jul 17.

Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

The purpose of this study was to evaluate temporal stability, multi-center reproducibility and the influence of covariates on a multimodal MR protocol for quantitative muscle imaging and to facilitate its use as a standardized protocol for evaluation of pathology in skeletal muscle. Quantitative T2, quantitative diffusion and four-point Dixon acquisitions of the calf muscles of both legs were repeated within one hour. Sixty-five healthy volunteers (31 females) were included in one of eight 3-T MR systems. Five traveling subjects were examined in six MR scanners. Average values over all slices of water-T2 relaxation time, proton density fat fraction (PDFF) and diffusion metrics were determined for seven muscles. Temporal stability was tested with repeated measured ANOVA and two-way random intraclass correlation coefficient (ICC). Multi-center reproducibility of traveling volunteers was assessed by a two-way mixed ICC. The factors age, body mass index, gender and muscle were tested for covariance. ICCs of temporal stability were between 0.963 and 0.999 for all parameters. Water-T2 relaxation decreased significantly (P < 10 ) within one hour by ~ 1 ms. Multi-center reproducibility showed ICCs within 0.879-0.917 with the lowest ICC for mean diffusivity. Different muscles showed the highest covariance, explaining 20-40% of variance for observed parameters. Standardized acquisition and processing of quantitative muscle MRI data resulted in high comparability among centers. The imaging protocol exhibited high temporal stability over one hour except for water T2 relaxation times. These results show that data pooling is feasible and enables assembling data from patients with neuromuscular diseases, paving the way towards larger studies of rare muscle disorders.
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http://dx.doi.org/10.1002/nbm.4119DOI Listing
September 2019

Natural course of scoliosis and lifetime risk of scoliosis surgery in spinal muscular atrophy.

Neurology 2019 07 4;93(2):e149-e158. Epub 2019 Jun 4.

From the Department of Neurology and Neurosurgery (C.A.W., F.A.S.d.K., M.S., L.A.M.O., F.-L.A., R.P.A.v.E., J.S., I.C., L.H.v.d.B., R.I.W., W-L.v.d.P), Department of Rehabilitation (M.V.), Department of Orthopedic Surgery (R.C.B., R.M.C.), Department of Pediatrics, Child Development and Exercise Centre (B.B), and Biostatistics & Research Support Julius Centre for Health Sciences and Primary Care (R.P.A.v.E.), University Medical Centre Utrecht, Utrecht University, the Netherlands.

Objective: To investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).

Methods: We analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.

Results: The lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years ( = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.

Conclusion: The lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.
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http://dx.doi.org/10.1212/WNL.0000000000007742DOI Listing
July 2019

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial).

BMJ Open 2018 07 30;8(7):e019932. Epub 2018 Jul 30.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.

Methods And Analysis: We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2-4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.

Ethics And Dissemination: The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.

Trial Registration Number: NCT02941328.
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http://dx.doi.org/10.1136/bmjopen-2017-019932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067401PMC
July 2018
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