Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers.Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
Twenty-three male and nine female hurdlers were filmed using three-dimensional methods during competition at the 1988 United States Olympic Trials. An entire four-step cycle was analyzed, including the clearances of the men's fifth hurdle and the women's fourth hurdle. The results showed an increase in vertical velocity and a decrease in forward horizontal velocity during the takeoff of the hurdle step. The forward velocity was recovered mainly in the second support phase after the hurdle. The downward motion of the center of mass (c.m.) was not stopped until the second support phase after the hurdle clearance. The peak of the c.m. parabola was almost directly over the hurdle in the men, and 0.30 m before the hurdle in the women. It was shown that the women used a parabola with a larger margin over the top of the hurdle than the men: A lower parabola would shorten the hurdle step, and would require the lengthening of the three interhurdle steps. It would also make the duration of the airborne phase too short, which would not give the legs enough time to prepare for landing after the execution of their motions over the hurdle. Therefore, women should not be coached to imitate the men's hurdle clearance technique.
Objective Infantile‐onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. Methods A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS‐sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. Results Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post‐hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). Interpretation These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile‐onset SMA. The power and utility of NeuroNEXT to provide “real‐world,” prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883–891
Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration : NCT01557400 .
Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.
Duchenne muscular dystrophy (DMD) is a rare, progressive, debilitating neuromuscular disease. The early childhood onset and debilitating nature of the disease necessitate decades of caretaking for most patients. Caregivers have a critical role in evaluating patients' physical functioning and/or response to treatment. Using DMD-specific caregiver-reported scales, the impact of delandistrogene moxeparvovec gene therapy on caregivers' perceived change in patient disease status or severity was evaluated using the Caregiver Global Impression of Change and Severity (CaGI-C and CaGI-S, respectively).
DAPENA, J. and C. MCDONALD. A three-dimensional analysis of angular momentum in the hammer throw. Med. Sci. Sports Exerc, Vol. 21, No. 2, pp. 206–220, 1989. Eight hammer throwers were studied using three-dimensional cinematography. The local term of angular momentum of each thrower (HTL) followed a wide conical path, while the remote term (HTR) and the hammer angular momentum (HH) followed much narrower conical paths. HT, the sum of (HTLand HTR, followed a conical path similar to that of HTL, although with smaller amplitude. HH, was half of a cycle out of phase with HT. It was also larger but followed a narrower conical path. As a result, the conical paths ofHH and HT counteracted each other, and Hs, the total angular momentum vector of the thrower-hammer system, had little conical motion. The paths of the angular momentum vectors, the trunk tilt, and the height of the hammer plane relative to the system center of mass were interrelated. Some throwers kept the hammer plane high and the trunk tilting back in all the turns; other throwers kept the hammer plane low and the trunk tilting forward in the early turns, but the hammer plane rose in their late turns and the trunk tilted back. Two theories were proposed to explain why the athletes who had forward trunk tilt in the early turns tilted backward in the final part of the throw.
Introduction Care Considerations supported by the Centers for Disease Control and Prevention for the management of Duchenne muscular dystrophy were published in 2010, but there has been limited study of implementation in the United States.Methods A questionnaire collecting information about standard care practices and perceived barriers was piloted by 9 clinic directors of facilities within the Muscular Dystrophy Surveillance, Tracking and Research network.Results Six clinic directors completed the questionnaire; 1 adult-only clinic was excluded.Over 80% adherence was found for 30 of 55 recommendations examined.Greatest variability was for initiation of corticosteroids, bone health monitoring, type of pulmonary function testing, and psychosocial management.Barriers included unclear guidelines, inadequate time and funding, family-specific barriers and lack of empirical support for some recommendations.Discussion This pilot study showed implementation of the 2010 Care Considerations, except for recommendations based largely on expert consensus.Complete adherence requires more studies and active promotion.
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