Use of a wearable device to assess sleep and motor function in Duchenne muscular dystrophy

2019 ◽  
Vol 61 (2) ◽  
pp. 198-204 ◽  
Author(s):  
Benjamin I. Siegel ◽  
Ayse Cakmak ◽  
Erik Reinertsen ◽  
Macarthur Benoit ◽  
Janet Figueroa ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Motor Function ◽  
Wearable Device

scholarly journals Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

2019 ◽  
Author(s):  
Sara Nagy ◽  
Patricia Hafner ◽  
Simone Schmidt ◽  
Daniela Rubino-Nacht ◽  
Sabine Schädelin ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Motor Function ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Open Label Extension ◽  
To Receive ◽  
Function Measure

Abstract BACKGROUND Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows besides its antitumor activity also antioxidant actions and regulatory roles in the calcium homeostasis. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo controlled phase 3 trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open label extension of the study will be offered to all participants. METHODS/DESIGN At least 71 ambulant and up to 20 non-ambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered to receive tamoxifen for further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in non-ambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative MRI of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed. DISCUSSION The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and non-ambulant DMD patients over 48 weeks. Motor function measure comprises the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double blind phase) compared to a delayed start can reduce disease progression more efficiently.

scholarly journals Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

2019 ◽  
Author(s):  
Sara Nagy ◽  
Patricia Hafner ◽  
Simone Schmidt ◽  
Daniela Rubino-Nacht ◽  
Sabine Schädelin ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Motor Function ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Open Label Extension ◽  
To Receive ◽  
Function Measure

Abstract BACKGROUND Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows besides its antitumor activity also antioxidant actions and regulatory roles in the calcium homeostasis. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo controlled phase 3 trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open label extension of the study will be offered to all participants. METHODS/DESIGN At least 71 ambulant and up to 20 non-ambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered to receive tamoxifen for further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in non-ambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative MRI of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed. DISCUSSION The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and non-ambulant DMD patients over 48 weeks. Motor function measure comprises the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double blind phase) compared to a delayed start can reduce disease progression more efficiently.

Recombinant human insulin‐like growth factor‐1 therapy for 6 months improves growth but not motor function in boys with Duchenne muscular dystrophy

2020 ◽  
Vol 61 (5) ◽  
pp. 623-631
Author(s):  
Meilan M. Rutter ◽  
Brenda L. Wong ◽  
James J. Collins ◽  
Hemant Sawnani ◽  
Michael D. Taylor ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Growth Factor ◽  
Muscular Dystrophy ◽  
Motor Function ◽  
Human Insulin ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin

scholarly journals Duchenne muscular dystrophy patients lacking the dystrophin isoforms Dp140 and Dp71 and mouse models lacking Dp140 have a more severe motor phenotype

2021 ◽  
Author(s):  
Mary Chesshyre ◽  
Deborah Ridout ◽  
Yasumasa Hashimoto ◽  
Yoko Ookubo ◽  
Silvia Torelli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Grip Strength ◽  
Mouse Models ◽  
Motor Function ◽  
Wild Type ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this. Methods Functional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice. Results In DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (p<0.01) and 4.9 points lower in group 3 than group 2 (p=0.05). Mean peak NSAA scores were 4.0 points lower in group 3 than group 1 (p<0.01), 2.4 points lower in group 3 than group 2 (p=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04). Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01). Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures. Conclusions DMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.

Characteristics of Disease Progression and Genetic Correlation in Ambulatory Iranian Boys With Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Gholamreza Zamani ◽  
Sareh Hosseinpour ◽  
Mahmoud Reza Ashrafi ◽  
Mahmoud Mohammadi ◽  
Reza Shervin Badv ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Motor Function ◽  
Pediatric Population ◽  
Disease Onset ◽  
Clinical History ◽  
Disease Diagnosis ◽  
The Mean ◽  
Mutation Type

Abstract Introduction: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations are progressive muscle weakness, impairment in walking and motor function leading to loss of ambulation by age of 13 years. Molecular studies are standard tests for diagnosis. This article describes the status of disease progression and genetic pattern in the Iranian affected boys and furthermore, concerns to find a correlation between the genotype and motor function phenotype of them. Methods This study was performed on 152 DMD patients. Clinical history including disease phenotype, steroid therapy data and the NorthStar Ambulatory Assessment (NSAA) score were all collected. Molecular diagnoses were confirmed by multiplex ligation dependent probe amplification and Next Generation Sequencing tests. Results We studied a total of 152 Iranian DMD patients. The mean age at disease onset was 4.04 ± 2.00 year and the mean age at diagnosis was 5.05 ± 2.08 year. The mean age of loss of ambulatory was 10.9 year. Contracture was seen in 38.9 %. The overall mean of NSAA total score versus age of the patients peaked at 4 year with mean NSAA score of 24. We assessed the yearly changes in the NSAA linear score for all cases based on mutation type and exon site. We found deletion mutation in 79.1%, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon was deletion exon 44 in our patients (5.3%) and the most common multiexon deletion was 45–50 and 45–52 exon equally with 4.6%. This study did not show any correlation between age at disease onset, loss of ambulation age and wheelchair dependency with mutation type but a correlation between contracture with mutation type was found. A significant deference in NSAA score were seen between deletion and nonsense groups at the age of 3 year (P = 0.036) and 3.5 years (p = 0.04). We couldn’t find any correlation among phenotype and Exon site. 91.1% had a history of corticosteroid taking and 54.1% of patient had compliance with rehabilitation. Conclusion This study has demonstrated the phenotype and mutational features of DMD boys and provide information of the disease natural motor history, disease progression and disease diagnosis with the management status of DMD in Iran. Achieved data will encourage the development of clinical trials and advance future molecular therapies in Iran.

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