Muscle strength and motor function in neuromuscular disorders. A clinical study of children and adolescents with spinal muscular atrophy, myotonic dystrophy, Duchenne muscular dystrophy and amyoplasia

Aim: The aims of this study were to investigate muscle strength and motor function in children and adolescents with four neuromuscular disorders; 1) spinal muscular atrophy (SMA), 2) myotonic dystrophy (DM), 3) Duchenne muscular dystrophy (DMD and 4) the amyoplasia form of arthrogryposis multiplex congenita. Further: 1) to analyze compensatory maneuvers due to muscle weakness in individuals with SMA, 2) to correlate motor function in individuals with DM with the size of the mutation, 3) to evaluate the long-term side effects and effects on muscle strength, motor function, vital capacity and development of scoliosis in boys with DMD treated with low-dose prednisone, and 4) to investigate how muscle strength and joint contractures affect motor function in individuals with amyoplasia and to relate current status to joint position at birth. Methods: 14 children and adolescents from western part of Sweden with SMA, 42 children and adolescents from western and southern Sweden with DM, 37 boys from western Sweden with DMD and 35 individuals from Sweden with amyoplasia participated in this study. In study 2, a control group of 42 age and gender-matched healthy children and adolescents was investigated. Medical records were reviewed and a clinical examination was performed. Isometric muscle strength was measured with an electronic hand-held dynamometer, contractures with an ordinary goniometer and motor function was assessed according to a scale designed for children with neuromuscular disorders. Results: 1) In children and adolescents with SMA profound muscle weakness was found in all assessed muscle groups compared to normal strength. Proximal weakness was greater than distal and lower limbs were more affected than upper limbs. Walking, transfer from lying or sitting to the standing position, and climbing stairs were possible in some of the individuals, despite marked reduction of muscle strength. Compensatory maneuvers described were reinforcement by using stronger upper limbs or distal muscle groups. 2) Children and adolescents with DM were significantly weaker than healthy controls in a majority of the assessed muscle groups. There was a great variation where some of the individuals had normal muscle strength. A strong correlation was found between motor function score and size of the mutation (rho=-0.743). Jumping, heel-standing and head-lifting in supine were difficult to perform, but few had difficulty in walking, running and stair-climbing. 3) Low-dose prednisolone treatment in boys with DMD delayed the time of loss of ambulation by at least 1.7 years and postponed development of scoliosis and contractures. There were also beneficial effects on muscle strength, motor function and vital capacity. The side effects were mild and long-term treatment was possible.4) In individuals with amyoplasia muscle strength affected motor function to a greater extent than joint contractures, although the joint contractures and joint position at birth also had an impact. Muscle strength was reduced in most of the investigated individuals. There was, however, heterogeneity and some of the patients had normal muscle strength in some of the investigated muscle groups. More attention should be paid at developing muscle strength, with early stimulation of active movement, and periods of immobilization should be minimized. Conclusions: SMA, DM, DMD and amyoplasia are heterogeneous conditions with a wide spectrum of muscle involvement. This investigation of muscle strength and motor function increases our knowledge concerning pattern and degree of muscle weakness in the different disorders, but also the impact of muscle weakness on motor function. The results have enhanced the possibilities of planning therapeutic interventions and the understanding of the prerequisites for everyday life in the children and adolescents with neuromuscular disorders

Low bone mineral density and reduced bone-specific alkaline phosphatase in 5q spinal muscular atrophy type 2 and type 3: A 2-year prospective study of bone health

AimIndividuals with spinal muscular atrophy (SMA) are at risk of developing skeletal problems. This study investigated bone mineral density (BMD), bone turnover markers and motor function in children and adolescents with SMA type 2 and type 3 over a two-year period. The effect of nusinersen was studied in a subgroup.MethodsSingle-centre study, including 20 patients, 2-18 years, of whom ten patients received nusinersen treatment. BMD was measured by dual-energy X-ray absorptiometry.ResultsAll patients had low BMD levels at baseline; mean Z-score -2.3 for total body less head (TBLH) and -2.9 for total hip left (THL). Significant correlations were found both at baseline and for the follow-up change for motor function and Z-scores (TBLH and THL). For the whole study group, reduced bone formation and unchanged bone resorption, assessed by bone-specific alkaline phosphatase (BALP) (p = 0.0006, ES = -0.83) and C-terminal cross-linking telopeptide of type I collagen (CTX), respectively, were found over the study period. However, BALP decreased less in the nusinersen treatment group, which suggests a positive development on bone mass in these patients.ConclusionBone health evaluation is important in follow-up programmes for SMA patients. Further investigations are warranted for individuals on survival motor neuron-targeted treatments.Funding Agencies|Neuroforbundet; Norrbacka-Eugeniastiftelsen; RBU Research Foundation; Norrbacka-Eugenia Foundation; Promobilia Research Foundation; Muskelfonden (the Research Foundation for Neuromuscular Disorders); Neurofoerbundet (the Swedish Patient Organization for Neurological Disorders); Region OEstergoetland</p

Comparison of ambulatory capacity and disease progression of Duchenne muscular dystrophy subjects enrolled in the drisapersen DMD114673 study with a matched natural history cohort of subjects on daily corticosteroids

Duchenne muscular dystrophy is a rare genetic disorder with life-limiting pathology. Drisapersen induces exon 51 skipping, thereby producing a shorter but functional dystrophin protein. The longest available data are from an open-label extension study (PRO051-02) treating 12 boys with drisapersen (6 mg/kg/week subcutaneously). The median change (range) from baseline to week 177 in six-minute walking distance (6MWD) was 8 (-263, 163) metres. The current analysis aimed to put the results from PRO051-02 in the context of natural progression by comparing the functional trajectory of drisapersen-treated subjects to a matched natural history (NH) cohort, treated by standard of care. Subjects were matched individually by age and 6MWD, as the primary analysis, and by age and rise from floor (RFF), as sensitivity analysis. A total of 75 NH subjects were available for 6MWD analysis, of which matching was possible for 9 ambulant drisapersen-treated subjects. None of the 6 "stable" (baseline 6MWD ≥330 metres) drisapersen-treated subjects lost ambulation vs 4 out of 10 matched NH subjects over a comparable timeframe (~3.4 years), compared with 2 out of 3 ambulant "in decline" drisapersen-treated subjects vs all 6 matched NH subjects. A total of 79 NH subjects were available for RFF analysis. For continuous ambulatory subjects (N = 4), the RFF decline was more pronounced in the NH cohort than in the drisapersen-treated subjects. In conclusion, a comparison of ambulant drisapersen-treated subjects with matched NH subjects showed a difference in functional trajectories over a timeframe of up to 3.4 years in favour of drisapersen.publisher: Elsevier articletitle: Comparison of ambulatory capacity and disease progression of Duchenne muscular dystrophy subjects enrolled in the drisapersen DMD114673 study with a matched natural history cohort of subjects on daily corticosteroids journaltitle: Neuromuscular Disorders articlelink: http://dx.doi.org/10.1016/j.nmd.2016.11.013 content_type: article copyright: © 2016 The Authors. Published by Elsevier B.V.status: publishe

Using a time-geographical diary method in order to facilitate reflections on changes in patterns of daily occupations

Objective and methods: Time-use methodologies have been proposed to be established research techniques when exploring aspects of daily occupations. In this study, two graphs illustrating the time arrangement of occupations as they appear in a continuous sequence were used in order to encourage individuals to reflect on their everyday life. The aim was to investigate the usefulness of a time-geographical diary method (using illustrative graphs) in combination with stimulated-recall interviews, to facilitate reflections on how patterns of daily occupations change over time and the causes that lie behind these changes. The study had a qualitative design. The participants were two working, married mothers, i.e. individuals considered to have highly complex patterns of daily occupations. The data analysis was performed by using thematic content analysis. Results: The results showed that the stimulated-recall interviews, based on the graphs, facilitated new insights that came to light concerning the scope of the participants' daily life. The method enabled the participants to reflect on their patterns of daily occupations and become aware of changes relevant to explain the causes for engaging in occupations the way they did. Conclusions: The method thus seems useful in research and practice for occupational therapists working with individuals with a need to change lifestyle

Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study

<div><p>Background</p><p>Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations.</p><p>Methods</p><p>This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73–80), followed by intermittent dosing (weeks 81–188).</p><p>Results</p><p>Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored “zero”. When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α₁-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72.</p><p>Conclusion</p><p>Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01910649?term=NCT01910649&rank=1" target="_blank">NCT01910649</a></p></div

Patient flow diagram.

<p>^aExcluding planned washout and off-drug periods.</p

Change from extension study baseline in 6MWD, by visit over 177 weeks.

<p>Data shown are for all subjects who completed the test at the extension study baseline. One subject (Subject 3) was non-ambulant at study entry and did not participate in any 6MWD tests, while another subject (Subject 4) was unable to complete the 6MWD test at the extension study baseline. Data for both of these subjects are not shown here. Subjects 1, 2, 5, 6, 7, 9, and 12 walked ≥330 m at extension study baseline; subjects 8, 10, and 11 walked <330 m at extension study baseline. 6MWD: six-minute walk distance.</p