Functional impairment in patients with myotonic dystrophy type 1 can be assessed by an ataxia rating scale (SARA)

Myotonic dystrophy type 1 (DM1) is not characterised by ataxia per se; however, DM1 and ataxia patients show similar disturbances in movement coordination often experiencing walking and balance difficulties, although caused by different underlying pathologies. This study aims to investigate the use of a scale previously described for the assessment and rating of ataxia (SARA) with the hypothesis that it could have utility in DM1 patients as a measure of disease severity and risk of falling. Data from 54 DM1 patients were pulled from the PHENO-DM1 natural history study for analysis. Mean SARA score in the DM1 population was 5.45 relative to the maximum score of eight. A flooring effect (score 0) was observed in mild cases within the sample. Inter-rater and test–retest reliability was high with intraclass coefficients (ICC) of 0.983 and 1.00, respectively. Internal consistency was acceptable as indicated by a Cronbach’s alpha of 0.761. Component analysis revealed two principle components. SARA correlated with: (1) all measures of muscle function tested, including quantitative muscle testing of ankle dorsiflexion (r = −0.584*), the 6 min walk test (r = −0.739*), 10 m walk test (r = 0.741*), and the nine hole peg test (r = 0.602*) and (2) measures of disease severity/burden, such as MIRS (r = 0.718*), MDHI (r = 0.483*), and DM1-Activ (r = −0.749*) (*p < 0.001). The SARA score was predicted by an interaction between modal CTG repeat length and age at sampling (r = 0.678, p = 0.003). A score of eight or above predicted the use of a walking aid with a sensitivity of 100% and a specificity of 85.7%. We suggest that further research is warranted to ascertain whether SARA or components of SARA are useful outcome measures for clinical trials in DM1. As a tool, it can be used for gathering information about disease severity/burden and helping to identify patients in need of a walking aid, and can potentially be applied in both research and healthcare settings

Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities

Abstract The muscular dystrophies are a heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness. These disorders present a large clinical variability regarding age of onset, patterns of skeletal muscle involvement, heart damage, rate of progression and mode of inheritance. Difficulties in classification are often caused by the relatively common sporadic occurrence of autosomal recessive forms as well as by intrafamilial clinical variability. Furthermore recent discoveries, particularly regarding the proteins linking the sarcolemma to components of the extracellular matrix, have restricted the gap existing between limb girdle (LGMD) and congenital muscular dystrophies (CMD). Therefore a renewed definition of boundaries between these two groups is required. Molecular genetic studies have demonstrated different causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. These novel skeletal muscle genes encode highly diverse proteins with different localization within or at the surface of the skeletal muscle fibre, such as the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), the extracellular matrix (a2 laminin, collagen VI), the sarcomere (telethonin, myotilin, titin, nebulin and ZASP), the muscle cytosol (calpain-3, TRIM32), the nucleus (emerin, lamin A/C) and the glycosilation pathway enzymes (fukutin and fukutin related proteins). The accumulating knowledge about the role of these different proteins in muscle pathology has led to a profound change in the original phenotype-based classification and shed new light on the molecular pathogenesis of these disorders.

Life expectancy in Duchenne Muscular Dystrophy : reproduced individual patient data meta-analysis

Objective: Duchenne Muscular Dystrophy (DMD) is a rare progressive disease, which is often diagnosed in early childhood, and leads to considerably reduced life-expectancy; due to its rarity, research literature and patient numbers are limited. To fully characterise the natural history, it is crucial to obtain appropriate estimates of the life-expectancy and mortality rates of patients with DMD. Methods: A systematic review of the published literature on mortality in DMD up until July 2020 was undertaken, specifically focusing on publications in which Kaplan-Meier (KM) survival curves with age as a time-scale were presented. These were digitised and individual patient data (IPD) reconstructed. The pooled IPD were analysed using the Kaplan-Meier estimator and parametric survival analysis models. Estimates were also stratified by birth cohort. Results: Of 1177 articles identified, 14 publications met the inclusion criteria and provided data on 2283 patients, of whom 1049 had died. Median life-expectancy was 22.0 years (95% CI: 21.2, 22.4). Analyses stratifying by three time-periods in which patients were born showed markedly increased life-expectancy in more recent patient populations; patients born after 1990 have a median life-expectancy of 28.1 years (95% CI 25.1, 30.3). Conclusions: This paper presents a full overview of mortality across the lifetime of a patient with DMD, and highlights recent improvements in survival. In the absence of large-scale prospective cohort studies or trials reporting mortality data for patients with DMD, extraction of IPD from the literature provides a viable alternative to estimating life-expectancy for this patient population

Natural history of Duchenne muscular dystrophy in the United Kingdom : a descriptive study using the Clinical Practice Research Datalink

Background Duchenne muscular dystrophy (DMD) is a rare, muscle-degenerative disease predominantly affecting males. Natural history models capture the full disease pathway under current care and combine with estimates of new interventions’ effects to assess cost-effectiveness by health technology decision-makers. These models require mortality estimates throughout a patient's lifetime, but rare disease datasets typically contain relatively few patients with short follow-ups. Alternative (published) sources of mortality data may therefore be required. Methods The Clinical Practice Research Datalink (CPRD) was evaluated as a source of mortality and natural history data for future economic evaluations of health technologies for DMD and rare diseases in general in the UK population. This retrospective longitudinal cohort study provides flexible parametric estimates of mortality rates and survival probabilities in the current UK DMD population through primary/secondary records in the CPRD since 1990. It also investigates clinically significant milestones such as corticosteroid use, spinal surgery, and cardiomyopathy in these patients. Results A total of 1121 male patients were included in the study, observed from 0.7 to 48.9 years. Median life expectancy was 25.64 years (95% confidence interval 24.73, 26.47), consistent with previous global estimates. This has improved to 26.47 (25.16, 27.89) years in patients born after 1990. The median ages at corticosteroid initiation, spinal surgery, ventilation, and cardiomyopathy diagnosis were 6.06 years (5.77, 6.29), 14.79 years (14.29, 15.09), 16.97 years (16.50, 18.31), and 15.26 years (14.22, 16.70), respectively. Conclusions Estimates of mortality in UK-based DMD patients are age-specific in a uniquely large and nationally representative sample from the CPRD

Is ongoing testosterone required after pubertal induction in Duchenne muscular dystrophy?

Glucocorticoids (GCs) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD) but cause pubertal delay. Pubertal induction with testosterone is recommended but longer-term outcome is unknown. Objective: To assess hypothalamic–pituitary–gonadal axis, muscle volume and function 5 years after pubertal induction. Methods: A prospective observational follow-up of a clinical study was conducted. 15 GC-treated males with DMD were treated with incremental testosterone for 2 years (end of regimen +2 years) then evaluated at +2.5 years and +5 y ears (final follow-up ~3 years after last injection). Data collected included testicular volume (TV), gonadotrophin, testosterone, inhibin B, muscle function, and limb muscle MRI. Results: Participants were 18.7 years (s.d. 1.6) at the final follow-up and had been on GC for 11.2 years (s.d. 2.2). Testosterone levels were similar at +2.5 years (8.6 nmol /L (s.d. 3.4) and 5 years (11.0 nmol/L (s.d. 6.1). TV increased from 2.8 mL ( s.d. 0.9) at +2 years to 7.1 mL (s.d. 1.8) then 10.6 mL (s.d. 3.5) at +2.5 years and +5.0 years (P < 0.001). Inhibin B levels increased from 55.6 pg/mL (s.d. 47.0) at baseline to 158.2 pg/mL ( s.d. 87.6), P =0.004 at 5 years but remained lower than reference values (mean 305 pg/mL). Muscle contractile bulk decreased. Interpretation: Pubertal induction with testosterone in DMD is associated with HPG axis activation and ongoing increases in inhibin B, TV, and testosterone concentrations. Some patients have normal levels which is promising regarding future fertility. Given the beneficial impact of testosterone on bone health, muscle, and well-being, monitoring testosterone levels in this population and supplementation of sub-optimal levels is important

Dual-energy X-ray absorptiometry measures of lean body mass as a biomarker for progression in boys with Duchenne muscular dystrophy

We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16 weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (p = 0.050) and arms (p < 0.001). The relationship between lean body mass at Week 49 and functional endpoints at Week 97 was evaluated. Changes in lean body mass at Week 49 in all regions except arms were significantly correlated with percent change from baseline in 4-stair climb (4SC) at Week 97. DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014

Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial

Introduction: The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo. Methods: The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score). Results: There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65–0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to “not obtainable” (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1–3.9, p = 0.0359). Conclusions: These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as “not obtainable” for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test

Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials

BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients to untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: Over 1,600 patient-years of follow-up (>700 patients) were studied from six real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-meter walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for non-genotypic prognostic factors. DISCUSSION: These findings suggest viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study