BACKGROUND: This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS: The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS: A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS: The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).
- MeSH
- dítě MeSH
- Duchennova muskulární dystrofie * genetika terapie MeSH
- dystrofin genetika MeSH
- konsensus MeSH
- lidé MeSH
- nesmyslný kodon MeSH
- oxadiazoly * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Izrael MeSH
- Řecko MeSH
- Švédsko MeSH
- východní Evropa MeSH
Dystrofinopatie predstavujú hereditárne podmienené neuromuskulárne ochorenia zo skupiny svalových dystrofií charakterizované úplnou absenciou alebo zníženou funkciou dystrofínového proteínu. Medzi dystrofinopatie radíme predovšetkým Duchennovu svalovú dystrofiu (DMD), Beckerovu svalovú dystrofiu (BMD) a DMD-asociovanú dilatačnú kardiomyopatiu (DCM). Vzhľadom na incidenciu ochorenia v populácii patria dystrofinopatie medzi najčastejšie neuromuskulárne ochorenia detského veku. V klinickom obraze sa typicky vyskytuje oneskorený motorický vývoj, progresívna svalová slabosť, pseudohypertrofie v oblasti lýtok a Gowersov príznak. Na základe klinických symptómov a pomocných vyšetrení (nález zvýšenej hodnoty kreatínkinázy) je následne diagnóza stanovená molekulárno- genetickým vyšetrením. V terapii je štandardne odporúčaná kortikosteroidná liečba pri súčasnom multidisciplinárnom manažmente pacienta v špecializovaných centrách pre neuromuskulárne ochorenia.
The dystrophinopathies are a spectrum of progressive muscular dystrophies that are caused by the absence of or decrease in the function of dystrophin protein. The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy (DCM). Due to the incidence in the population, dystrophinopathy is one of the most common neuromuscular diseases of childhood. In clinical picture we can usually find delayed motor development, progressive muscle weakness, calf pseudohypertrophy and Gowers‘ sign. Based on clinical symptoms and initial tests (the finding of elevated creatine kinase), the diagnosis is made by molecular genetic testing. In therapy, corticosteroid therapy is recommended as standard treatment with multidisciplinary management of the patient in specialized centres for neuromuscular diseases.
Duchennova a Beckerova svalová dystrofie, které jsou způsobeny mutacemi v genu pro dystrofin, patří k nejčastějším svalovým onemocněním dětského věku. Příznaky zahrnují vlastní motorické postižení, později se přidává i respirační insuficience a srdeční potíže, které bývají mezi 25.-30. rokem věku příčinou smrti. Kromě hybného postižení nacházíme u celé řady pacientů neuropsychiatrické poruchy zahrnující zejména poruchy intelektu, poruchy autistického spektra, poruchu aktivity a pozornosti a obsedantně kompulzivní chorobu. Podle publikovaných studií je jejich incidence u těchto pacientů vyšší, než je tomu v běžné populaci. Pravděpodobným vysvětlením je nedostatek dystrofinu v neuronech.
Duchenne/Becker muscular dystrophy, caused by mutations in dystrophin gene,is one of the most frequent muscular dystrophies. Symptoms of DMD include typical movement problems, cardiomyopathy and respiratory failure most often occur in the third decade. In many patients we can find not only movement problems but also neuropsychiatric disorders, esp. autism spectrum disorders, attention-deficit hyperactivity disorder and obsessive-compulsive disorder. Their incidence is higher than in other population. Probabaly it due to lack of dystrophin in neurons.
AIMS: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. METHODS AND RESULTS: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. CONCLUSIONS: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.
- MeSH
- dilatační kardiomyopatie * epidemiologie genetika MeSH
- dospělí MeSH
- dystrofin genetika MeSH
- funkce levé komory srdeční MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nemoci svalů * MeSH
- prevalence MeSH
- retrospektivní studie MeSH
- srdeční selhání * epidemiologie MeSH
- tepový objem MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy.
- MeSH
- dilatační kardiomyopatie genetika metabolismus patologie MeSH
- Duchennova muskulární dystrofie genetika metabolismus patologie MeSH
- dystrofin nedostatek genetika MeSH
- kardiomyocyty metabolismus patologie MeSH
- kardiovaskulární systém metabolismus patologie MeSH
- kmenové buňky metabolismus patologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myokard metabolismus patologie MeSH
- myši inbrední mdx genetika MeSH
- myši MeSH
- poškození DNA genetika MeSH
- protoonkogenní proteiny c-kit genetika MeSH
- regulace genové exprese genetika MeSH
- stárnutí genetika patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We describe the association of Becker muscular dystrophy (BMD) derived heart failure with the impairment of tissue homeostasis and remodeling capabilities of the affected heart tissue. We report that BMD heart failure is associated with a significantly decreased number of cardiovascular progenitor cells, reduced cardiac fibroblast migration, and ex vivo survival.BACKGROUND: Becker muscular dystrophy belongs to a class of genetically inherited dystrophin deficiencies. It affects male patients and results in progressive skeletal muscle degeneration and dilated cardiomyopathy leading to heart failure. It is a relatively mild form of dystrophin deficiency, which allows patients to be on a heart transplant list. In this unique situation, the explanted heart is a rare opportunity to study the degenerative process of dystrophin-deficient cardiac tissue. Heart tissue was excised, dissociated, and analyzed. The fractional content of c-kit+/CD45- cardiovascular progenitor cells (CVPCs) and cardiac fibroblast migration were compared to control samples of atrial tissue. Control tissue was obtained from the hearts of healthy organ donor's during heart transplantation procedures. RESULTS: We report significantly decreased CVPCs (c-kit+/CD45-) throughout the heart tissue of a BMD patient, and reduced numbers of phase-bright cells presenting c-kit positivity in the dystrophin-deficient cultured explants. In addition, ex vivo CVPCs survival and cardiac fibroblasts migration were significantly reduced, suggesting reduced homeostatic support and irreversible tissue remodeling. CONCLUSIONS: Our findings associate genetically derived heart failure in a dystrophin-deficient patient with decreased c-kit+/CD45- CVPCs and their resilience, possibly hinting at a lack of cardioprotective capability and/or reduced homeostatic support. This also correlates with reduced plasticity of the explanted cardiac tissue, related to the process of irreversible remodeling in the BMD patient's heart.
- MeSH
- dilatační kardiomyopatie * MeSH
- Duchennova muskulární dystrofie * MeSH
- dystrofin MeSH
- kmenové buňky MeSH
- lidé MeSH
- myokard MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cardiomyocytes (CM) placed on microelectrode array (MEA) were simultaneously probed with cantilever from atomic force microscope (AFM) system. This electric / nanomechanical combination in real time recorded beating force of the CMs cluster and the triggering electric events. Such "organ-on-a-chip" represents a tool for drug development and disease modeling. The human pluripotent stem cells included the WT embryonic line CCTL14 and the induced dystrophin deficient line reprogrammed from fibroblasts of a patient affected by Duchenne Muscular Dystrophy (DMD, complete loss of dystrophin expression). Both were differentiated to CMs and employed with the AFM/MEA platform for diseased CMs' drug response testing and DMD characterization. The dependence of cardiac parameters on extracellular Ca2+ was studied. The differential evaluation explained the observed effects despite variability of biological samples. The β-adrenergic stimulation (isoproterenol) and antagonist trials (verapamil) addressed ionotropic and chronotropic cell line-dependent features. For the first time, a distinctive beating-force relation for DMD CMs was measured on the 3D cardiac in vitro model.
- MeSH
- biosenzitivní techniky * MeSH
- buněčná diferenciace genetika MeSH
- Duchennova muskulární dystrofie patofyziologie MeSH
- dystrofin genetika MeSH
- fibroblasty účinky léků ultrastruktura MeSH
- indukované pluripotentní kmenové buňky metabolismus ultrastruktura MeSH
- isoprenalin farmakologie MeSH
- kardiomyocyty cytologie MeSH
- kontrakce myokardu genetika fyziologie MeSH
- lidé MeSH
- mikroelektrody MeSH
- mikroskopie atomárních sil MeSH
- verapamil farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Duchenne muscular dystrophy (DMD) affects 1:3500-5000 newborn boys and manifests with progressive skeletal muscle wasting, respiratory failure and eventual heart failure. Symptoms show different onset from patients' childhood to the second decade of age. We reprogrammed fibroblasts from two independent DMD patients with a complete loss of dystrophin expression, carrying deletions of exons 45-50 and 48-50. The resulting hiPSCs show expression of pluripotency markers (NANOG, OCT4, SSEA4), differentiation capacity into all three germ layers, normal karyotype, genetic identity to the originating parental fibroblasts and the patient-specific dystrophin mutation.
- MeSH
- buněčná diferenciace MeSH
- buněčné linie cytologie metabolismus MeSH
- dítě MeSH
- Duchennova muskulární dystrofie genetika metabolismus patofyziologie MeSH
- dystrofin genetika metabolismus MeSH
- exony MeSH
- indukované pluripotentní kmenové buňky cytologie metabolismus MeSH
- lidé MeSH
- mladiství MeSH
- oktamerní transkripční faktor 3 genetika metabolismus MeSH
- sekvenční delece MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Duchennova a Beckerova svalová dystrofie, které jsou způsobeny mutacemi v genu pro dystrofin, patří k nejčastějším svalovým onemocněním dětského věku. První příznaky zahrnují obvykle opoždění motorického vývoje, potíže s běháním nebo s chůzí do a ze schodů. Klasickým příznakem je i tzv. Gowersův manévr. Později se přidává i respirační insuficience a srdeční potíže, které bývají mezi 25.–30. rokem věku příčinou smrti. Diagnostika je založena na klinickém obraze a výsledcích pomocných vyšetření (zejména na extrémní elevaci CK). Potvrzení diagnózy probíhá na molekulárně genetické úrovni. Onemocnění je stále kauzálně nevyléčitelné, nicméně pokroky ve vedení multidisciplinární péče a nové možnosti léčby výrazně prodloužily život a zlepšily jeho kvalitu u těchto pacientů.
Duchenne/Becker muscular dystrophy, caused by mutations in dystrophin gene,is one of the most frequent muscular dystrophies. First symptoms of DMD include delayed motor milestones, difficult running or climbing stairs. Boys with DMD use the Gower´s maneuver to arise from floor. Cardiomyopathy and respiratory failure most often occur in the third decade. Diagnostical process is based on clinical picture, blood tests results (esp. elevated CK) and confirmation on molecular genetic base. Treatment aims to control symptoms. New drugs in clinical practice as well as in clinical trials together with better multidisciplinary care can prolong patients life and improve its quality.
- MeSH
- Duchennova muskulární dystrofie * diagnóza etiologie terapie MeSH
- dystrofin fyziologie genetika nedostatek MeSH
- genetická terapie metody MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- lidé MeSH
- svalová slabost etiologie MeSH
- svalové dystrofie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- Duchennova muskulární dystrofie farmakoterapie MeSH
- dystrofin MeSH
- genetická terapie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
