Journal of Neuromuscular Diseases - Volume 11, issue 3

Authors: Rabbia, Michael | Guridi Ormazabal, Maitea | Staunton, Hannah | Veenstra, Klaas | Eggenspieler, Damien | Annoussamy, Mélanie | Servais, Laurent | Strijbos, Paul

Article Type: Research Article

Abstract: Background: Stride Velocity 95th Centile (SV95C) is the first wearable device-derived clinical outcome assessment (COA) to receive European Medicines Agency (EMA) qualification as a primary endpoint in ambulant patients with Duchenne muscular dystrophy (DMD) aged ≥4 years. Objective: To compare SV95C—in its first-ever clinical trial application as a secondary endpoint—with established motor function COAs used in the trial (Four-Stair Climb [4SC] velocity, North Star Ambulatory Assessment [NSAA], and Six-Minute Walk Distance [6MWD]). Methods: SV95C was a secondary endpoint in a subset (n  = 47) of participants in the SPITFIRE/WN40227 trial of taldefgrobep alfa, which was …discontinued due to lack of clinical benefit. Participants in the ≤48-week SV95C sub-study were 6–11 years old and received corticosteroids for ≥6 months pre-treatment. Pearson correlations were used to compare SV95C with the other COAs. Responsiveness and changes over time were respectively assessed via standardized response means (SRMs) based on absolute changes and mixed models for repeated measures. Results: SV95C change at Week 24 was –0.07 m/s, with limited variability (standard deviation: 0.16, n  = 27). The SRM for SV95C indicated moderate responsiveness to clinical change at the earliest timepoint (Week 12, n  = 46), while those of the other COAs did not indicate moderate responsiveness until Week 36 (6MWD, n  = 33) or Week 48 (4SC velocity, n  = 20; NSAA total score, n  = 20). Baseline correlations between SV95C and other COAs were strong (r  = 0.611–0.695). Correlations between SV95C change from baseline to Week 48 and changes in other COAs were moderate to strong (r  = 0.443–0.678).∥ Conclusions: Overall, SV95C demonstrated sensitivity to ambulatory decline over short intervals, low variability, and correlation with established COAs. Although the negative trial precluded demonstration of SV95C’s sensitivity to drug effect, these findings support the continued use of SV95C in DMD clinical trials. Show more

Keywords: muscular, dystrophy, digital endpoints, ambulation, stride velocity 95th centile, clinical trials

DOI: 10.3233/JND-230188

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 701-714, 2024

Authors: Nakamura, Akinori | Matsumura, Tsuyoshi | Takeshima, Yasuhiro | Kuru, Satoshi | Imazaki, Manami | Nonomura, Hidenori | Kaiya, Hisanobu

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease. Clinical evaluation of DMD uses patient-intensive motor function tests, and the recent development of wearable devices allows the collection of a variety of biometric information, including physical activity. Objective: In this study, we examined differences in physical activity and heart rate variability (HRV) between patients with DMD and healthy subjects using a wearable device, and investigated any association between these parameters and motor function in patients with DMD. Methods: Participants were 7 patients with DMD and 8 healthy males, whose physical activity and HRV were …provided by a wearable device. These data were used to investigate the relationship between both physical activity and HRV parameters and timed motor functional tests [Time to stand from supine, 10-meter walking time (10MWT), North Star Ambulatory Assessment (NSAA), and 6-minute walking test (6MWT)] in patients with DMD. Results: Results of 24-hours physical activity, fat burning, total number of steps and active distance, average step rate, average exercise intensity during walking, exercise, degree of forward lean during walking, maximum heart rate, normalized low frequency power (LF norm), and maximum exercise intensity in patients with DMD were lower than those in control subjects. Physical activity and HRV parameters did not correlate with the time to stand from supine. The 10MWT positively correlated with average heart rate, while NSAA negatively correlated with average heart rate, total frequency power (TF), and very low frequency power (VLF) during arousal. The 6MWT negatively correlated with ratio LF/high frequency power (HF). CONCLUSIONS: Physical activity and HRV indices that differ from those of normal children and that correlate with motor function assessment may serve as digital biomarkers. Show more

Keywords: Duchenne muscular dystrophy, timed motor functional test, physical activity, heart rate variability, wearable device

DOI: 10.3233/JND-230142

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 715-724, 2024

Authors: Campanale, Carmen | Laghetti, Paola | Saltarella, Ilaria | Altamura, Concetta | Canioni, Eleonora | Iosa, Emanuele | Maggi, Lorenzo | Brugnoni, Raffaella | Tacconi, Paolo | Desaphy, Jean-François

Article Type: Research Article

Abstract: Background: The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. Methods: Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro …electrophysiology, site-directed mutagenesis and heterologous expression were collected. Results: A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A ) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude. Conclusions: The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia. Show more

Keywords: Sodium channel myotonia, SCN4A gene, next-generation sequencing, short exercise test, electrophysiology

DOI: 10.3233/JND-230134

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 725-734, 2024