Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ...ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying mutations using new gene-editing technologies and corticosteroid analogs with better safety profiles offers renewed hope for many individuals with DMD and their families.
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. ...Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.
Abstract The muscular dystrophies are a broad group of hereditary muscle diseases with variable severity. Population-based prevalence estimates have been reported but pooled estimates are not ...available. We performed a systematic review of worldwide population-based studies reporting muscular dystrophies prevalence and/or incidence using MEDLINE and EMBASE databases. The search strategy included key terms related to muscular dystrophies, incidence, prevalence and epidemiology. Two reviewers independently reviewed all abstracts, full text articles and abstracted data using standardized forms. Pooling of prevalence estimates was performed using random effect models. 1104 abstracts and 167 full text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The studies differed widely in their approaches to case ascertainment, resulting in significant methodological heterogeneity and varied data quality. The pooled prevalence of DMD and BMD was 4.78 (95% CI 1.94–11.81) and 1.53 (95% CI 0.26–8.94) per 100,000 males respectively. The incidence of DMD ranged from 10.71 to 27.78 per 100,000. This is the first meta-analysis of worldwide prevalence estimates for muscular dystrophies. There is a need for more epidemiological studies addressing global estimates on incidence and prevalence of muscular dystrophies, utilizing standardized diagnostic criteria as well as multiple sources of case ascertainment.
Neuromuscular ultrasound is a rapidly evolving technique for diagnosing, monitoring and facilitating treatment of patients with muscle and nerve disorders. It is a portable point-of-care technology ...that is non-invasive, painless and without ionizing radiation. Ultrasound can visualize muscle texture alterations indicating dystrophy or denervation, changes in size and anatomic continuity of nerve fascicles, and its dynamic imaging capabilities allow capturing of contractions and fasciculations. Ultrasound can also provide real-time guidance for needle placement, and can sometimes make a diagnosis when electromyography is not tolerated or not informative anymore. This review will focus on the technical and practical aspects of ultrasound as an imaging technique for muscles and nerves. It will discuss basic imaging principles, hardware and software setup, and provide examples of ultrasound use for visualizing muscle and nerve abnormalities with accuracy and confidence. The review is intended as a practical "how-to" guide to get started with neuromuscular ultrasound in daily practice.
The Role of PIEZO2 in Human Mechanosensation Chesler, Alexander T; Szczot, Marcin; Bharucha-Goebel, Diana ...
The New England journal of medicine,
10/2016, Letnik:
375, Številka:
14
Journal Article
Recenzirano
Odprti dostop
The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory ...functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms.
We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation.
Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception.
Our results show that PIEZO2 is a determinant of mechanosensation in humans. (Funded by the National Institutes of Health Intramural Research Program.).
An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease.
To ...evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping.
This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019.
Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion.
Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function.
Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean range 5.7% 3.2-10.3 of normal; 80 mg/kg per week: mean range 5.9% 1.1-14.4 of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit.
Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed.
ClinicalTrials.gov Identifier: NCT02740972.
Significance Duchenne muscular dystrophy (DMD) is a rare and devastating muscle disease caused by mutations in the X-linked DMD gene (which encodes the dystrophin protein). Serum biomarkers hold ...significant potential as objective phenotypic measures of DMD disease state, as well as potential measures of pharmacological effects of and response to therapeutic interventions. Here we describe a proteomics approach to determine serum levels of 1,125 proteins in 93 DMD patients and 45 controls. The study identified 44 biomarkers that differed significantly between patients and controls. These data are being made available to DMD researchers and clinicians to accelerate the search for new diagnostic, prognostic, and therapeutic approaches.
Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy–Cincinnati Children’s Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.
Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term ...effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.
For this prospective cohort study, we enrolled male patients aged 2–28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.
440 patients were enrolled during two recruitment periods (2006–09 and 2012–16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1–4·4 years and upper limb milestones by 2·8–8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1–2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22–1·00; p=0·0501).
In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.
US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.
Advances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology ...exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented.
Purpose of review
The purpose of this review is to summarize the current and emerging therapies for Duchenne muscular dystrophy (DMD).
Recent findings
Coinciding with new standardized care ...guidelines, there are a growing number of therapeutic options to treat males with DMD. Treatment of the underlying pathobiology, such as micro-dystrophin gene replacement, exon skipping, stop codon read-through agents, and utrophin modulators showed variable success in animal and human studies. Symptomatic therapies to target muscle ischemia, enhance muscle regeneration, prevent muscle fibrosis, inhibit myostatin, and reduce inflammation are also under investigation.
Summary
DMD is a complex, heterogeneous degenerative disease. The pharmacological and technological achievements made in recent years, plus timely supportive interventions will likely lead to an improved quality of life for many individuals with DMD.
PDF
