A paper a day Archives • World Duchenne

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Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular Dystrophy

#apaperaday: Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular Dystrophy

Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy in the Muscular Dystrophy Surveillance, Tracking, and Research Network Today’s pick is from World Muscle Society journal Neuromuscular Disorders by Paramdothy et al on the factors that influence mortality in Duchenne patients in the USA who were part of MD STARNet doi 10.1016/j.nmd.2022.04.008. Duchenne is a severe progressive muscle wasting disease sadly leading to loss of function & premature death. With improved care, the age of death has increased in the past decades. However, no study has been done yet in the USA. Here authors looked into the MDStarnet database IMAGE Looking into causes of mortality is looking into the past. Authors considered only patients born between 1982 and 1999 as they are old enough to maybe have died. As you can see in the graph below ~25% of 30 year olds are still alive. However, sadly many died earlier IMAGE The mean age of death in the USA was 23.7 years, which is similar to previous reports from other countries. While these analyses may seem a bit morbid, they can inform us about which aspects can protect against mortality. This is analysis the authors did as well. Protective: using steroids (continued after loss of ambulation), using a cough assist and having undergone scoliosis surgery. No difference was found between type of steroid. No effects of use of cardiac medication was seen - however, most patients were not treated presymptomatic Authors discuss that a Japanese study suggests that treating patients presymptomatically (as the current care standards also suggest) was protective. The protective effect of scoliosis surgery is a bit puzzling and was not found by most other studies. Generally patients who develop scoliosis severe enough to require surgery are very severely affected. Possibly the patients undergoing scoliosis attended more expert care sites, while others - though needing surgery - were not offered the option (my own speculation) Authors also identified that non-Hispanic black Duchenne patients had an increased risk of mortality. They noticed before that the average age of diagnosis and (thus) age of initiating steroids were later. This may have played a role. Socioeconomic status may also have contributed Authors discuss limitations of their study e.g. this study only involves USA patients who attended US Starnet clinics so it is not representative of all USA patients. Another limitation is that this focuses on patients born long ago who did not have current multidisciplinary care There is no solution for this limitation as we cannot look into the future. However, it is clear that many care guidelines that are in play (steroid use, cough assist) have a clear impact not only on disease progression but also on mortality.

#apaperaday: Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy

Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy

#apaperaday: Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD

Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD

#apaperaday: Evaluation of DNA segments in 2′-modified RNA sequences in designing efficient splice switching antisense oligonucleotides

Evaluation of DNA segments in 2′-modified RNA sequences in designing efficient splice switching antisense oligonucleotides

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Genetic modifiers of upper limb function in Duchenne muscular dystrophy Ascension day special from Journal of Neurology by Sabbatini et al with Luca Bello on the influence of genetic modifiers on upper limb function decline in Duchenne patients. The confirmed suspects for ambulatory loss were assessed for the upper limb. Doi 10.1007/s00415-012-11133-8. While all Duchenne patients go through the relentless loss of one function after another, there is variability in the speed of loss. Eg for Duchenne patients on corticosteroids loss of ambulation can occur before age 10 to after age 15 years. This can be influenced by dystrophin, where patients with very low dystrophin levels have a slower progression than patients without dystrophin (eg exon 44 skippable patients). It can also be influenced by genetic variation in other genes influencing eg fibrosis or inflammation Multiple modifiers have been found to influence loss of ambulation age, where variants are protective vs detrimental. SPP1 was first, but also LTBP4, CD40, ACTN3 and THBS1 and others were reported. So far effects on upper limb function decline was not studied Here authors study the effect of modifiers (SPP1, CD40, LTPB4 and ACTN3) on the performance upper limb (PUL) scale in a cohort of 137 Italian patients (with 636 assessments) and Brooke scale in 340 patients (2895 assessments). They corrected for steroid effects as patients on steroids had significantly better arm function than those not using steroids. There was no significant association for total PUL and the modifiers. For PUL they also looked at subscales for shoulder, elbow and distal arm. CD40 modifier had an effect on shoulder & distal domains, while ACTN3 had an effect on elbow & distal. For the Brooke scale, SPP1 and CD40 influenced outcomes. Authors also looked at dystrophin mutation effects, and were unable to find a protective effect of exon 44 skip mutation They saw protective effects for some exons (exon 45 and exon 8) but these groups are very small and thus this may be influenced by other aspects (e.g. age of the subgroups vs average age etc). Authors discuss that their study shows the natural history of limb function decline Shoulder function decline starts early (~7.5y), followed by elbow and distal function. Interestingly, LTBP4 associations were not found, while this modifier showed the most robust effects on loss of ambulation. For ACTN3 it is the opposite, with a more robust effect on arm function Authors discuss that the ACTN3 modifier has an impact on strength and primarily in type 2 muscle fibers, which are more prominent in upper limb than lower limb in Duchenne patients. I commend the authors for looking into these aspects - arm function is very important for Duchenne I do wonder though why authors did not (also) look in a milestone focused way. e.g. loss of a particular arm function as was done for ambulation. I understand the PUL and Brooke look at this with lower numbers reflecting loss of a function on an aggregated way For genetic modifier discovery a milestone driven approach may be easier (from a statistic/modeling perspective). Since not all ambulation modifiers influence arm function, it would be good to study modifiers not (robustly) influencing loss of ambulation for arm function effects. More work is needed on genetic modifiers in general, and on their effect on various functional aspects in particular. I commend the authors for taking a first step for the upper limb function aspects.

#apaperaday: Genetic modifiers of upper limb function in Duchenne muscular dystrophy

Genetic modifiers of upper limb function in Duchenne muscular dystrophy.

#apaperaday: Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis

Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis

#apaperaday: Adult North Star Network (ANSN): Consensus Document for Therapists Working with Adults with Duchenne Muscular Dystrophy (DMD) - Therapy Guidelines

Consensus Document for Therapists Working with Adults with Duchenne Muscular Dystrophy (DMD) - Therapy Guidelines

#apaperaday: Age at diagnosis for Duchenne muscular dystrophy: Why we must do better

Age at diagnosis for Duchenne muscular dystrophy: Why we must do better

#apaperaday: Therapeutic Strategies for Dystrophin Replacement in Duchenne Muscular Dystrophy

Therapeutic Strategies for Dystrophin Replacement in Duchenne Muscular Dystrophy

#apaperaday: Development of a novel startle response task in Duchenne muscular dystrophy

Development of a novel startle response task in Duchenne muscular dystrophy

#apaperaday: Cognition of the mothers of patients with Duchenne muscular dystrophy

Cognition of the mothers of patients with Duchenne muscular dystrophy

#apaperaday: CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype

CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype

#apaperaday: Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment

Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment

#apaperaday: Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmdmdx/J Mouse

Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmdmdx/J Mouse

#apaperaday: Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy

Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy

#apaperaday: Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy

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

#apaperaday: Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases

Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases.

#apaperaday: Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy

Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy

#apaperaday: Measuring carer quality of life in Duchenne muscular dystrophy

Measuring carer quality of life in Duchenne muscular dystrophy: a systematic review of the reliability and validity of self-report instruments using COSMIN

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls

#apaperaday: Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy

Suitability of the North Star Ambulatory Assessment for comparisons with external controls

#apaperaday: Martial Arts Training for Boys with Duchenne Muscular Dystrophy

Martial Arts Training for Boys with Duchenne Muscular Dystrophy

#apaperaday: Cardio-respiratory and phenotypic rescue of dystrophin/utrophin-deficient mice by combination therapy

Cardio-respiratory and phenotypic rescue of dystrophin/utrophin-deficient mice by combination therapy.

#apaperaday: Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

#apaperaday: Treating Duchenne Muscular Dystrophy: The Promise of Stem Cells, Artificial Intelligence, and Multi-Omics

Treating Duchenne Muscular Dystrophy: The Promise of Stem Cells, Artificial Intelligence, and Multi-Omics

#apaperaday: Cardiorespiratory management of Duchenne muscular dystrophy: emerging therapies, neuromuscular genetics, and new clinical challenges

Cardiorespiratory management of Duchenne muscular dystrophy: emerging therapies, neuromuscular genetics, and new clinical challenges

#apaperaday: Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy

#apaperaday: A Long-Term Study Evaluating the Effects of Nicorandil Treatment on Duchenne Muscular Dystrophy-Associated Cardiomyopathy in mdx Mice

A Long-Term Study Evaluating the Effects of Nicorandil Treatment on Duchenne Muscular Dystrophy-Associated Cardiomyopathy in mdx Mice

Today’s pick is by Campos et al from Frontiers in cell & developmental biology on the effect of simvastatin on muscle development doi 10.3389/fcell.2022.778901 Simvastatin & other statins reduce the production of cholesterol & in this way reduce blood cholesterol levels. They are a well known treatment for hypercholesterolemia. However, they can also cause muscle pain, tiredness and weakness and even breakdown of muscle (rhabdomyolysis). Here authors studied the effect of simvastatin on zebrafish muscle development. They benefit from the fact that zebrafish larvae are transparent. Using high doses of simvastatin resulted in shorter, 'bendy' fish, while with low concentrations a reduction in myofibrils was seen. Also the movement of the fish/larvae was reduced with simvastatin treatment in a dose dependent manner when applied early (6 hrs) or later (11 hrs) post fertilization. Desmin and mitochondria were mislocalized (top normal, middle mild phenotype, bottom severe phenotype) IMAGE When authors supplied cholesterol and simvastatin most of the deficits were normalized, suggesting that the results are due to a reduction in cholesterol. Authors further studied the potential effect on regeneration in primary muscle cell cultures from chicken. This showed that with simvastatin proliferation was reduced. Authors speculate that likely due to lower levels of cholesterol, membranes are less stable and cells less able to proliferate and later differentiate (which makes sense to me - you need cholesterol/lipids to divide) Authors discuss that their work focuses mainly on embryonic development of muscle and therefore the mechanism of simvastatin on postnatal muscle is not yet known and needs to be further studied. They state that the effects observed are dose dependent. Given that the effects are dose dependent I am disappointed that authors do not explain how the doses they used in their experiments correlate to the doses used to treat humans. How physiologically relevant are these studies? Maybe doses are much higher than human doses. Authors also discuss the simvastatin work in the mdx mouse model for Duchenne, outlining the controversy of some papers showing a slower disease progression and others (including our group) no effect (see earlier #apaperaday discussions). I was hoping the authors would have an explanation for the discrepancy and the fact that using the same dose and route of administration, ~100 fold differences in blood simvastatin levels are achieved. However, they do not (neither do I so not blame them). Authors indicate that more work is needed in human cell cultures (2D and 3D) and animal models to elucidate this further. I agree but would like to add that physiologically relevant doses should be used in the in vitro systems.

#apaperaday: Simvastatin and Muscle: Zebrafish and Chicken Show that the Benefits are not Worth the Damage

Simvastatin and Muscle: Zebrafish and Chicken Show that the Benefits are not Worth the Damage

#apaperaday: Pfizer Eyes Resuming Phase III Enrollment, Investigates Phase Ib Death Tied to Duchenne Muscular Dystrophy Candidate

Pfizer Eyes Resuming Phase III Enrollment, Investigates Phase Ib Death Tied to Duchenne Muscular Dystrophy Candidate.

#apaperaday: CRISPR editing as a therapeutic strategy for Duchenne muscular dystrophy

CRISPR editing as a therapeutic strategy for Duchenne muscular dystrophy—anti-Cas9 immune response casts its shadow over safety and efficacy.

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#apaperaday: Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular Dystrophy

#apaperaday: Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy

#apaperaday: Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD

#apaperaday: Evaluation of DNA segments in 2′-modified RNA sequences in designing efficient splice switching antisense oligonucleotides

#apaperaday: Genetic modifiers of upper limb function in Duchenne muscular dystrophy

#apaperaday: Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis

#apaperaday: Adult North Star Network (ANSN): Consensus Document for Therapists Working with Adults with Duchenne Muscular Dystrophy (DMD) - Therapy Guidelines

#apaperaday: Age at diagnosis for Duchenne muscular dystrophy: Why we must do better

#apaperaday: Therapeutic Strategies for Dystrophin Replacement in Duchenne Muscular Dystrophy

#apaperaday: Development of a novel startle response task in Duchenne muscular dystrophy

#apaperaday: Cognition of the mothers of patients with Duchenne muscular dystrophy

#apaperaday: CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype

#apaperaday: Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment

#apaperaday: Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmdmdx/J Mouse

#apaperaday: Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy

#apaperaday: Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy

#apaperaday: Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases

#apaperaday: Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy

#apaperaday: Measuring carer quality of life in Duchenne muscular dystrophy

#apaperaday: Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy

#apaperaday: Martial Arts Training for Boys with Duchenne Muscular Dystrophy

#apaperaday: Cardio-respiratory and phenotypic rescue of dystrophin/utrophin-deficient mice by combination therapy

#apaperaday: Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

#apaperaday: Treating Duchenne Muscular Dystrophy: The Promise of Stem Cells, Artificial Intelligence, and Multi-Omics

#apaperaday: Cardiorespiratory management of Duchenne muscular dystrophy: emerging therapies, neuromuscular genetics, and new clinical challenges

#apaperaday: Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy

#apaperaday: A Long-Term Study Evaluating the Effects of Nicorandil Treatment on Duchenne Muscular Dystrophy-Associated Cardiomyopathy in mdx Mice

#apaperaday: Simvastatin and Muscle: Zebrafish and Chicken Show that the Benefits are not Worth the Damage

#apaperaday: Pfizer Eyes Resuming Phase III Enrollment, Investigates Phase Ib Death Tied to Duchenne Muscular Dystrophy Candidate

#apaperaday: CRISPR editing as a therapeutic strategy for Duchenne muscular dystrophy

World Duchenne Organization announces Accredited Duchenne Centers Program

Official WDAD2022 Event: Women and Duchenne

World Duchenne Organization Leadership Award for Professor Muntoni