PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1302393)

Clipboard (0)
None

Related Articles

1.  Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients 
Acta Myologica  2012;31(2):121-125.
Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.
The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).
The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.
This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.
PMCID: PMC3476854  PMID: 23097603
Duchenne; survival; cardiomyopathy
2.  Twenty-four hour noninvasive ventilation in Duchenne muscular dystrophy: A safe alternative to tracheostomy 
BACKGROUND:
Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative.
METHODS:
The authors’ experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported.
RESULTS:
The mean (± SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8±3.5 years and 0.90±0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8±3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2 and, predominantly, by end-tidal CO2. While the results suggested improved CO2 levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years).
CONCLUSIONS:
Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone.
PMCID: PMC3628652  PMID: 23457679
Duchenne; Lung volume recruitment; Neuromuscular; Noninvasive ventilation; Ventilation
3.  Characteristics and Outcomes of Cardiomyopathy in Children with Duchenne or Becker Muscular Dystrophy: A Comparative Study from The Pediatric Cardiomyopathy Registry 
American heart journal  2008;155(6):998-1005.
Objective
To determine in pediatric Duchenne (DMD) and Becker (BMD) muscular dystrophy or other dilated cardiomyopathies (ODCM) whether outcomes differ by diagnosis.
Background
Children with dilated cardiomyopathy are treated as a single undifferentiated group.
Methods
This cohort study of 128 children with DMD, 15 with BMD, and 312 with ODCM uses outcome measures of LV size and function, death, heart transplant, and death or transplant.
Results
At cardiomyopathy diagnosis, the DMD and BMD groups had similar mean ages (14.4 and 14.6 years), prevalence of CHF (30% and 33%), and LV fractional shortening (FS) z-scores (median, −5.2 for DMD and −6.7 for BMD). The BMD group had more severe mitral regurgitation (P=.05) and a higher mean LV end-diastolic dimension Z-score than the DMD group (2.9±1.5 vs. 1.2±1.9, P=.002). DMD group survival was lower than in BMD or ODCM groups (P=.06) at 5-years (57%, 100%, and 71% respectively). In BMD, 25% received cardiac transplants within 0.4 years of cardiomyopathy diagnosis. The combined DMD and BMD group had less LV dilation and a closer-to-normal LVFS at cardiomyopathy diagnosis than the ODCM group. After 2 years, LV dilation increased and LVFS did not change in the combined DMD and BMD group; for OCDM patients, LV dilation did not progress and LVFS improved.
Conclusions
Children with DMD and cardiomyopathy have a higher mortality. BMD has a high heart transplantation rate in the 5 years after diagnosis of cardiomyopathy. Serial echocardiography demonstrates a different disease course for DMD and BMD patients compared with ODCM patients.
doi:10.1016/j.ahj.2008.01.018
PMCID: PMC2729548  PMID: 18513510
Muscular dystrophy; neuromuscular disease; cardiomyopathy; heart failure; pediatric; Duchenne; Becker
4.  Can outcomes in Duchenne muscular dystrophy be improved by public reporting of data? 
Neurology  2013;80(6):583-589.
Objective:
To review current approaches for obtaining patient data in Duchenne muscular dystrophy (DMD) and consider how monitoring and comparing outcome measures across DMD clinics could facilitate standardized and improved patient care.
Methods:
We reviewed annual standardized data from cystic fibrosis (CF) clinics and DMD care guidelines and consensus statements; compared current approaches to obtain DMD patient data and outcome measures; and considered the best method for implementing public reporting of outcomes, to drive improvements in health care delivery.
Results:
Current methods to monitor DMD patient information (MD STARnet, DuchenneConnect, and TREAT-NMD) do not yet provide patients with comparative outcome data. The CF patient registry allows for reporting of standard outcomes across clinics and is associated with improved CF outcomes. A similar patient registry is under development for the Muscular Dystrophy Association (MDA) clinic network. Suggested metrics for quality care include molecular diagnosis, ambulatory status and age at loss of ambulation, age requiring ventilator support, and survival.
Conclusions:
CF longevity has increased by almost 33% from 1986 to 2010, in part due to a CF patient registry that has been stratified by individual care centers since 1999, and publically available since 2006. Implementation of outcome reporting for MDA clinics might promote a similar benefit to patients with DMD.
doi:10.1212/WNL.0b013e318282334e
PMCID: PMC3589293  PMID: 23382369
5.  Characteristics of Japanese Duchenne and Becker muscular dystrophy patients in a novel Japanese national registry of muscular dystrophy (Remudy) 
Background
Currently, clinical trials for new therapeutic strategies are being planned for Duchenne and Becker muscular dystrophies (DMD/BMD). However, it is difficult to obtain adequate numbers of patients in clinical trials. As solutions to these problems, patient registries are an important resource worldwide, especially in rare diseases such as DMD/BMD.
Methods
We developed a national registry of Japanese DMD/BMD patients in collaboration with TREAT-NMD. The registry includes male Japanese DMD/BMD patients whose genetic status has been confirmed by genetic analysis. The registry includes patients throughout Japan.
Results
As of February 2012, 583 DMD and 105 BMD patients were registered. Most individuals aged less than 20 years. In terms of genetic mutations of registrants of DMD and BMD, deletion of exons was the most frequent (61.4% and 79.0%) followed by point mutations (24.5% and 14.3%) and duplications (13.6% and 4.8%), respectively. 43.6% of DMD are capable of walking, and 76.2% of BMD registrants are able to walk. 41.1% of DMD registrants in the database were treated using steroids. 29.5% of DMD and 23.8% of BMD registrants were prescribed one cardiac medicine at least. 22% of DMD used ventilator support, and non-invasive support was common. Small numbers of DMD and BMD registrants, only 3.9% and 1.0% of them, have received scoliosis surgery. 57 (9.8%) patients were eligible to clinical trial focused on ‘skipping’ exon 51.
Conclusions
The Remudy has already demonstrated utility in clinical researches and standardization of patients care for DMD/BMD. This new DMD/BMD patient registry facilitates the synchronization of clinical drug development in Japan with that in other countries.
doi:10.1186/1750-1172-8-60
PMCID: PMC3639029  PMID: 23601510
Duchenne and Becker muscular dystrophy; Neuromuscular disorder; National registry; TREAT-NMD; Registry of muscular dystrophy (Remudy), Japan
6.  Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy 
Thorax  1998;53(11):949-952.
BACKGROUND—Respiratory failure is the commonest cause of death in patients with Duchenne muscular dystrophy (DMD). Life expectancy is less than one year once diurnal hypercapnia develops. This study examines the effects of nasal intermittent positive pressure ventilation (NIPPV) on survival in symptomatic Duchenne patients with established ventilatory failure.
METHODS—Nocturnal NIPPV was applied in 23 consecutive patients with DMD of mean (SD) age 20.3 (3.4) years who presented with diurnal and nocturnal hypercapnia.
RESULTS—One year and five year survival rates were 85% (95% CI 69 to 100) and 73% (95% CI 53 to 94), respectively. Early changes in arterial blood gas tensions following NIPPV occurred with mean (SD) PO2 increasing from 7.6 (2.1) kPa to 10.8 (1.3) kPa and mean (SD) PCO2 falling from 10.3 (4.5) kPa to 6.1 (1.0) kPa. Improvements in arterial blood gas tensions were maintained over five years. Health perception and social aspects of SF-36 health related quality of life index were reported as equivalent to other groups with non-progressive disorders using NIPPV.
CONCLUSION—Nasal ventilation is likely to increase survival in hypercapnic patients with Duchenne muscular dystrophy and should be considered as a treatment option when ventilatory failure develops.


PMCID: PMC1745110  PMID: 10193393
7.  Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial 
The Lancet. Neurology  2014;14(2):153-161.
Summary
Background
Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease.
Methods
In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546.
Findings
Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1.0 [IQR 0.3–2.2]vs2.2 [1.3–3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo.
Interpretation
In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy.
Funding
BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.
doi:10.1016/S1474-4422(14)70318-7
PMCID: PMC4361281  PMID: 25554404
8.  Online Self-Report Data for Duchenne Muscular Dystrophy Confirms Natural History and Can Be Used to Assess for Therapeutic Benefits  
PLoS Currents  2014;6:ecurrents.md.e1e8f2be7c949f9ffe81ec6fca1cce6a.
To assess the utility of online patient self-report outcomes in a rare disease, we attempted to observe the effects of corticosteroids in delaying age at fulltime wheelchair use in Duchenne muscular dystrophy (DMD) using data from 1,057 males from DuchenneConnect, an online registry. Data collected were compared to prior natural history data in regard to age at diagnosis, mutation spectrum, and age at loss of ambulation. Because registrants reported differences in steroid and other medication usage, as well as age and ambulation status, we could explore these data for correlations with age at loss of ambulation. Using multivariate analysis, current steroid usage was the most significant and largest independent predictor of improved wheelchair-free survival. Thus, these online self-report data were sufficient to retrospectively observe that current steroid use by patients with DMD is associated with a delay in loss of ambulation. Comparing commonly used steroid drugs, deflazacort prolonged ambulation longer than prednisone (median 14 years and 13 years, respectively). Further, use of Vitamin D and Coenzyme Q10, insurance status, and age at diagnosis after 4 years were also significant, but smaller, independent predictors of longer wheelchair-free survival. Nine other common supplements were also individually tested but had lower study power. This study demonstrates the utility of DuchenneConnect data to observe therapeutic differences, and highlights needs for improvement in quality and quantity of patient-report data, which may allow exploration of drug/therapeutic practice combinations impractical to study in clinical trial settings. Further, with the low barrier to participation, we anticipate substantial growth in the dataset in the coming years.
doi:10.1371/currents.md.e1e8f2be7c949f9ffe81ec6fca1cce6a
PMCID: PMC4207635  PMID: 25635234
9.  Long term non-invasive ventilation in the community for patients with musculoskeletal disorders: 46 year experience and review 
Thorax  2000;55(1):4-11.
BACKGROUND—A study was undertaken to assess the long term physiological and clinical outcome in 79 patients with musculoskeletal disorders (73 neuromuscular, six of the chest wall) who received non-invasive ventilation for chronic respiratory failure over a period of 46years.
METHODS—Vital capacity (VC) and carbon dioxide tension (PCO2) before and after initiation of ventilation, type and duration of ventilatory assistance, the need for tracheostomy, and mortality were retrospectively studied in 48 patients who were managed with mouth/nasal intermittent positive pressure ventilation (M/NIPPV) and 31 who received body ventilation. The two largest groups analysed were 45 patients with poliomyelitis and 15 with Duchenne's muscular dystrophy. Twenty five patients with poliomyelitis received body ventilation (for a mean of 290 months) and 20 were supported by M/NIPPV (mean 38 months). All 15 patients with Duchenne's muscular dystrophy were ventilated by NIPPV (mean 22months).
RESULTS—Fourteen patients with poliomyelitis on body ventilation (56%) but only one on M/NIPPV, and 10 of 15 patients (67%) with Duchenne's muscular dystrophy eventually received tracheostomies for ventilatory support. Five patients with other neuromuscular disorders required tracheostomies. Twenty of 29 tracheostomies (69%) were provided because of progressive disease and hypercarbia which could not be controlled by non-invasive ventilation; the remaining nine were placed because of bulbar dysfunction and aspiration related complications. Nine of 10 deaths occurred in patients on body ventilation (six with poliomyelitis), although the causes of death were varied and not necessarily related to respiratory complications. A proportionately greater number of patients on M/NIPPV (67%) reported positive outcomes (improved sense of wellbeing and independence) than did those on body ventilation (29%, p<0.01). However, other than tracheostomies and deaths, negative outcomes in the form of machine/interface discomfort and self-discontinuation of ventilation also occurred at a rate 2.3 times higher than in the group who received body ventilation. None of the six patients with chest wall disorders (all on M/NIPPV) required tracheostomy or died. Hospital admission rates increased nearly eightfold in patients receiving body ventilation (all poliomyelitis patients) compared with before ventilation (p<0.01) while in those supported by M/NIPPV they were reduced by 36%.
CONCLUSIONS—Non-invasive ventilation (NIV) in the community over prolonged periods is a feasible although variably tolerated form of management in patients with neuromuscular disorders. While patients who received body ventilation were followed the longest (mean 24 years), the need for tracheostomy and deaths occurred more often in this group (most commonly in the poliomyelitis patients). Despite a number of discomforts associated with M/NIPPV, a larger proportion of patients experienced improved wellbeing, independence, and ability to perform daily activities.


doi:10.1136/thorax.55.1.4
PMCID: PMC1745585  PMID: 10607795
10.  Natural Ventilation for the Prevention of Airborne Contagion 
PLoS Medicine  2007;4(2):e68.
Background
Institutional transmission of airborne infections such as tuberculosis (TB) is an important public health problem, especially in resource-limited settings where protective measures such as negative-pressure isolation rooms are difficult to implement. Natural ventilation may offer a low-cost alternative. Our objective was to investigate the rates, determinants, and effects of natural ventilation in health care settings.
Methods and Findings
The study was carried out in eight hospitals in Lima, Peru; five were hospitals of “old-fashioned” design built pre-1950, and three of “modern” design, built 1970–1990. In these hospitals 70 naturally ventilated clinical rooms where infectious patients are likely to be encountered were studied. These included respiratory isolation rooms, TB wards, respiratory wards, general medical wards, outpatient consulting rooms, waiting rooms, and emergency departments. These rooms were compared with 12 mechanically ventilated negative-pressure respiratory isolation rooms built post-2000. Ventilation was measured using a carbon dioxide tracer gas technique in 368 experiments. Architectural and environmental variables were measured. For each experiment, infection risk was estimated for TB exposure using the Wells-Riley model of airborne infection. We found that opening windows and doors provided median ventilation of 28 air changes/hour (ACH), more than double that of mechanically ventilated negative-pressure rooms ventilated at the 12 ACH recommended for high-risk areas, and 18 times that with windows and doors closed (p < 0.001). Facilities built more than 50 years ago, characterised by large windows and high ceilings, had greater ventilation than modern naturally ventilated rooms (40 versus 17 ACH; p < 0.001). Even within the lowest quartile of wind speeds, natural ventilation exceeded mechanical (p < 0.001). The Wells-Riley airborne infection model predicted that in mechanically ventilated rooms 39% of susceptible individuals would become infected following 24 h of exposure to untreated TB patients of infectiousness characterised in a well-documented outbreak. This infection rate compared with 33% in modern and 11% in pre-1950 naturally ventilated facilities with windows and doors open.
Conclusions
Opening windows and doors maximises natural ventilation so that the risk of airborne contagion is much lower than with costly, maintenance-requiring mechanical ventilation systems. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection. Natural ventilation costs little and is maintenance free, and is particularly suited to limited-resource settings and tropical climates, where the burden of TB and institutional TB transmission is highest. In settings where respiratory isolation is difficult and climate permits, windows and doors should be opened to reduce the risk of airborne contagion.
In eight hospitals in Lima, opening windows and doors maximised natural ventilation and lowered the risk of airborne infection. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection.
Editors' Summary
Background.
Tuberculosis (TB) is a major cause of ill health and death worldwide, with around one-third of the world's population infected with the bacterium that causes it (Mycobacterium tuberculosis). One person with active tuberculosis can go on to infect many others; the bacterium is passed in tiny liquid droplets that are produced when someone with active disease coughs, sneezes, spits, or speaks. The risk of tuberculosis being transmitted in hospital settings is particularly high, because people with tuberculosis are often in close contact with very many other people. Currently, most guidelines recommend that the risk of transmission be controlled in certain areas where TB is more likely by making sure that the air in rooms is changed with fresh air between six and 12 times an hour. Air changes can be achieved with simple measures such as opening windows and doors, or by installing mechanical equipment that forces air changes and also keeps the air pressure in an isolation room lower than that outside it. Such “negative pressure,” mechanically ventilated systems are often used on tuberculosis wards to prevent air flowing from isolation rooms to other rooms outside, and so to prevent people on the tuberculosis ward from infecting others.
Why Was This Study Done?
In many parts of the world, hospitals do not have equipment even for simple air conditioning, let alone the special equipment needed for forcing high air changes in isolation rooms and wards. Instead they rely on opening windows and doors in order to reduce the transmission of TB, and this is called natural ventilation. However, it is not clear whether these sorts of measures are adequate for controlling TB transmission. It is important to find out what sorts of systems work best at controlling TB in the real world, so that hospitals and wards can be designed appropriately, within available resources.
What Did the Researchers Do and Find?
This study was based in Lima, Peru's capital city. The researchers studied a variety of rooms, including tuberculosis wards and respiratory isolation rooms, in the city's hospitals. Rooms which had only natural measures for encouraging airflow were compared with mechanically ventilated, negative pressure rooms, which were built much more recently. A comparison was also done between rooms in old hospitals that were naturally ventilated with rooms in newer hospitals that were also naturally ventilated. The researchers used a particular method to measure the number of air changes per hour within each room, and based on this they estimated the risk of a person with TB infecting others using a method called the Wells-Riley equation. The results showed that natural ventilation provided surprisingly high rates of air exchange, with an average of 28 air changes per hour. Hospitals over 50 years old, which generally had large windows and high ceilings, had the highest ventilation, with an average of 40 air changes per hour. This rate compared with 17 air changes per hour in naturally ventilated rooms in modern hospitals, which tended to have lower ceilings and smaller windows. The rooms with modern mechanical ventilation were supposed to have 12 air changes per hour but in reality this was not achieved, as the systems were not maintained properly. The Wells-Riley equation predicted that if an untreated person with tuberculosis was exposed to other people, within 24 hours this person would infect 39% of the people in the mechanically ventilated room, 33% of people in the naturally ventilated new hospital rooms, and only 11% of the people in the naturally ventilated old hospital rooms.
What Do These Findings Mean?
These findings suggest that natural methods of encouraging airflow (e.g., opening doors and windows) work well and in theory could reduce the likelihood of TB being carried from one person to another. Some aspects of the design of wards in old hospitals (such as large windows and high ceilings) are also likely to achieve better airflow and reduce the risk of infection. In poor countries, where mechanical ventilation systems might be too expensive to install and maintain properly, rooms that are designed to naturally achieve good airflow might be the best choice. Another advantage of natural ventilation is that it is not restricted by cost to just high-risk areas, and can therefore be used in many different parts of the hospital, including emergency departments, outpatient departments, and waiting rooms, and it is here that many infectious patients are to be found.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040068.
Information from the World Health Organization on tuberculosis, detailing global efforts to prevent the spread of TB
The World Health Organization publishes guidelines for the prevention of TB in health care facilities in resource-limited settings
Tuberculosis infection control in the era of expanding HIV care and treatment is discussed in an addendum to the above booklet
The Centers for Disease Control have published guidelines for preventing the transmission of mycobacterium tuberculosis in health care settings
Wikipedia has an entry on nosocomial infections (diseases that are spread in hospital). Wikipedia is an internet encyclopedia anyone can edit
A PLoS Medicine Perspective by Peter Wilson, “Is Natural Ventilation a Useful Tool to Prevent the Airborne Spread of TB?” discusses the implications of this study
doi:10.1371/journal.pmed.0040068
PMCID: PMC1808096  PMID: 17326709
11.  Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect 
Human Gene Therapy  2013;24(9):797-806.
Abstract
Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene transfer. In a trial of intramuscular adeno-associated virus (AAV)-mediated delivery of a therapeutic minidystrophin construct, we identified in two of six subjects the presence of a population of T cells that had been primed to recognize dystrophin epitopes before transgene delivery. As the presence of preexisting T cell immunity may have a significant effect on the success of therapeutic approaches for restoring dystrophin, we sought to determine the prevalence of such immunity within a DMD cohort from our Muscular Dystrophy Association clinic. Dystrophin-specific T cell immunity was evaluated in subjects with DMD who were either receiving the glucocorticoid steroid prednisone (n=24) or deflazacort (n=29), or who were not receiving steroids (n=17), as well as from normal age-matched control subjects (n=21). We demonstrate that increasing age correlates with an increased risk for the presence of anti-dystrophin T cell immunity, and that treatment with either corticosteroid decreases risk compared with no treatment, suggesting that steroid therapy in part may derive some of its benefit through modulation of T cell responses. The frequency of dystrophin-specific T cells detected by enzyme-linked immunospot assay was lower in subjects treated with deflazacort versus prednisone, despite similar overall corticosteroid exposure, suggesting that the effects of the two corticosteroids may not be identical in patients with DMD. T cells targeted epitopes upstream and downstream of the dystrophin gene mutation and involved the CD4+ helper and/or CD8+ cytotoxic subsets. Our data confirm the presence of preexisting circulating T cell immunity to dystrophin in a sizable proportion of patients with DMD, and emphasize the need to consider this in the design and interpretation of clinical gene therapy trials.
Flanigan and colleagues characterize the prevalence of preexisting dystrophin-specific T cells in Duchenne muscular dystrophy (DMD) patients. They identify CD4+ and CD8+ T cell populations targeting epitopes upstream and downstream of dystrophin mutations in a significant fraction of patients. They further demonstrate a lower frequency of dystrophin-specific T cells in patients receiving glucocorticoid therapy. These findings suggest important considerations for future DMD gene therapy trials and offer new insight into the mechanism of glucocorticoid therapy for DMD.
doi:10.1089/hum.2013.092
PMCID: PMC3768239  PMID: 24010700
12.  Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice 
PLoS Medicine  2009;6(5):e1000083.
James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy.
Background
The loss of dystrophin compromises muscle cell membrane stability and causes Duchenne muscular dystrophy and/or various forms of cardiomyopathy. Increased expression of the dystrophin homolog utrophin by gene delivery or pharmacologic up-regulation has been demonstrated to restore membrane integrity and improve the phenotype in the dystrophin-deficient mdx mouse. However, the lack of a viable therapy in humans predicates the need to explore alternative methods to combat dystrophin deficiency. We investigated whether systemic administration of recombinant full-length utrophin (Utr) or ΔR4-21 “micro” utrophin (μUtr) protein modified with the cell-penetrating TAT protein transduction domain could attenuate the phenotype of mdx mice.
Methods and Findings
Recombinant TAT-Utr and TAT-μUtr proteins were expressed using the baculovirus system and purified using FLAG-affinity chromatography. Age-matched mdx mice received six twice-weekly intraperitoneal injections of either recombinant protein or PBS. Three days after the final injection, mice were analyzed for several phenotypic parameters of dystrophin deficiency. Injected TAT-μUtr transduced all tissues examined, integrated with members of the dystrophin complex, reduced serum levels of creatine kinase (11,290±920 U versus 5,950±1,120 U; PBS versus TAT), the prevalence of muscle degeneration/regeneration (54%±5% versus 37%±4% of centrally nucleated fibers; PBS versus TAT), the susceptibility to eccentric contraction-induced force drop (72%±5% versus 40%±8% drop; PBS versus TAT), and increased specific force production (9.7±1.1 N/cm2 versus 12.8±0.9 N/cm2; PBS versus TAT).
Conclusions
These results are, to our knowledge, the first to establish the efficacy and feasibility of TAT-utrophin-based constructs as a novel direct protein-replacement therapy for the treatment of skeletal and cardiac muscle diseases caused by loss of dystrophin.
Editors' Summary
Background
Muscular dystrophies are genetic (inherited) diseases in which the body's muscles gradually weaken and degenerate. The commonest and most severe muscular dystrophy—Duchenne muscular dystrophy—affects 1 in 3,500 boys (girls can be carriers of the disease but rarely have any symptoms). At birth, these boys seem normal but the symptoms of their disease begin to appear in early childhood. Affected children may initially have difficulty walking or find it to hard to sit or stand independently. As they age, their muscle strength progressively declines and most affected boys are confined to a wheelchair by the time they are 12 years old. The muscles involved in breathing also weaken and the heart muscle becomes enlarged. Few boys with Duchenne muscular dystrophy live beyond their early 20 s, usually dying from breathing or heart problems. At present there is no cure for Duchenne muscular dystrophy. However, physical therapy and treatment with steroids can prolong the ability of patients to walk, and assisted ventilation can help with their breathing.
Why Was This Study Done?
In all muscular dystrophies, one of the proteins needed to build and maintain healthy muscles is missing or nonfunctional because of a genetic change (mutation). In Duchenne muscular dystrophy the mutation is in dystrophin, a protein that is involved in the formation of the dystrophin–glycoprotein complex. This complex normally sits in the membranes that surround muscle fibers and protects these membranes from damage during muscle contraction. Consequently, in Duchenne muscular dystrophy, the muscle fiber membranes become damaged and eventually the muscle fibers die. Thus, if functional dystrophin could be introduced into the muscles of patients with Duchenne muscular dystrophy, it might be possible to reduce their symptoms and prolong their lives. Indeed, the effects of dystrophin deficiency in the dystrophin-deficient mdx mouse can be reduced by the introduction of an artificial gene that expresses dystrophin or the closely related protein utrophin. Unfortunately, this gene therapy approach has not yet been effectively demonstrated in humans. In this study, therefore, the researchers investigate whether utrophin protein can be introduced directly into dystrophin-deficient mouse muscles by exposing the muscle cells to utrophin fused to the protein transduction domain of the HIV-1 TAT protein. Most proteins will not cross cell membranes, but proteins fused to this cell-penetrating domain readily enter many cell types, including muscle cells.
What Did the Researchers Do and Find?
The researchers injected full-length utrophin fused to the TAT protein transduction domain (TAT-Utr) and a short, “micro” version of utrophin fused to the same domain (TAT-μUtr) into the abdomens of mdx mice and looked to see where the proteins ended up. After two injections, both proteins were present in a wide range of tissues and organs, including several types of muscle. However, the levels of TAT-Utr were much lower than those of TAT-μUtr. Next, the researchers injected another group of mdx mice with TAT-μUtr six times over three weeks. Again, TAT-μUtr was present in all the tissues that the researchers examined. Furthermore, μUtr–glycoprotein complexes formed in the TAT-μUtr injected mdx mice and the membrane integrity and overall health of the dystrophin-deficient muscles of the mdx mice improved compared to mdx mice treated with saline. Finally, the researchers report, TAT-μUtr injections greatly improved the contractile performance of the muscles of the mdx mice.
What Do These Findings Mean?
These findings provide the first demonstration that injection of TAT-utrophin protein fusions may provide a way to treat muscular dystrophies caused by the loss of dystrophin. However, although this direct protein-replacement therapy looks hopeful, approaches that work in animals do not necessarily work in people. In particular, for this approach to work in patients with muscular dystrophy, it would be necessary to give frequent, high-dose injections of the TAT-μUtr fusion protein, a process that could eventually trigger a deleterious immune response. Nevertheless, the researchers suggest that by combining this novel approach with other approaches that also increase utrophin expression, it might be possible to prevent or delay the development of the symptoms of Duchenne muscular dystrophy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000085.
The US National Institute of Neurological Disorders and Stroke provides information on muscular dystrophy and ongoing research into possible treatments (in English and Spanish)
The US National Human Genome Research Institute also provides basic information on Duchenne muscular dystrophy and links to additional resources
The UK National Health Service Choices Web site has pages for patients and caregivers on muscular dystrophy
The Nemours Foundation provides information about muscular dystrophy for parents, children, and teenagers
For links to further resources on muscular dystrophy, see also MedlinePlus
doi:10.1371/journal.pmed.1000083
PMCID: PMC2680620  PMID: 19478831
13.  Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study 
Lancet  2011;378(9791):595-605.
Summary
Background
We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy.
Method
We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597.
Findings
19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts.
Interpretation
The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy.
Funding
UK Medical Research Council; AVI BioPharma.
doi:10.1016/S0140-6736(11)60756-3
PMCID: PMC3156980  PMID: 21784508
14.  Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials 
Brain  2011;134(12):3544-3556.
Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy.
doi:10.1093/brain/awr291
PMCID: PMC3235564  PMID: 22102647
Becker muscular dystrophy; Duchenne muscular dystrophy; nNOS; dystrophin-associated glycoprotein complex; therapy
15.  Clinical and Genetic Characterization of Manifesting Carriers of DMD Mutations 
Neuromuscular disorders : NMD  2010;20(8):499-504.
Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in fifteen manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchene muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X chromosome inactivation pattern was skewed toward nonrandom in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.
doi:10.1016/j.nmd.2010.05.010
PMCID: PMC2944769  PMID: 20630757
manifesting carriers; dystrophinopathy; DMD; dystrophin; X-chromosome inactivation; Duchenne muscular dystrophy; Becker muscular dystrophy
16.  Dystromirs as Serum Biomarkers for Monitoring the Disease Severity in Duchenne Muscular Dystrophy 
PLoS ONE  2013;8(11):e80263.
Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy (BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls.
We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials.
Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly the remaining muscle mass in DMD.
doi:10.1371/journal.pone.0080263
PMCID: PMC3840009  PMID: 24282529
17.  CINRG Duchenne Natural History Study demonstrates insufficient diagnosis and treatment of cardiomyopathy in Duchenne muscular dystrophy 
Muscle & nerve  2014;50(2):250-256.
Introduction
Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD).
Methods
A cross-sectional analysis of clinical data from a multi-institutional, international CINRG DMD Natural History Study of 340 DMD patients aged 2 to 28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%.
Results
231 participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47/174), and it was significantly associated with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P>0.68). In patients with cardiomyopathy, 57 % (27/47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15/127) of patients without cardiomyopathy.
Discussion
Echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.
doi:10.1002/mus.24163
PMCID: PMC4081523  PMID: 24395289
cardiomyopathy; Duchenne muscular dystrophy; glucocorticoid; echocardiogram; natural history
18.  Long-term ventilation of patients with Duchenne muscular dystrophy: experiences at the Neuromuscular Centre Ulm 
Acta Myologica  2012;31(3):170-178.
The various measures used to treat the symptoms of Duchenne muscular dystrophy (DMD), i.e. medication with steroids, early operation on contractures and spine deformities as well as cardiac diagnostics and therapy, should always be accompanied by careful monitoring of the patient's respiratory status. Therapy for respiratory failure, in particular long-term ventilation, is now generally accepted as essential for DMD patients. The provision of assisted ventilation has made a decisive contribution to the quality of life for older patients and the stigma hitherto attached to it as being merely a means of keeping a patient comfortable towards the end of life has now been dispelled. Even outside the hospital, assisted ventilation has become routine. These days it is not uncommon for patients on assisted ventilation to have their life extended by 10 years or more.
Non-invasive ventilation is sufficient if used concomitantly with coughing aids. Before undergoing orthopaedic surgery the patient' s respiratory status has to be carefully assessed in order to minimize the risk of perioperative complications. Feeding and swallowing problems may develop if the patient has a scoliosis of the cervical spine region, even if he has had thoraco-lumbar spine surgery. There is still insufficient awareness of this potential problem in relation to respiratory care.
Interdisciplinary collaboration between hospitals, general practitioners, muscle and respiratory centres, as well as advocacies and self-help groups is vital. The administration of aids to support DMD patients is now facilitated by guidelines drawn up by several centres of excellence. Here we mainly describe the historic development of respiratory care at the Ulm Neuromuscular Centre.
PMCID: PMC3631799  PMID: 23620648
Duchenne muscular dystrophy; respiratory failure; non-invasive ventilation; increased survival
19.  Late Gadolinium Enhancement: Precursor to Cardiomyopathy in Duchenne Muscular Dystrophy? 
Background
Progressive cardiomyopathy is a common cause of death in Duchenne muscular dystrophy (DMD), presumably secondary to fibrosis of the myocardium. The posterobasal and left lateral free wall of the left ventricle (LV) are initial sites of myocardial fibrosis pathologically. The purposes of this study were to assess whether cardiac magnetic resonance imaging (CMRI), utilizing late gadolinium enhancement (LGE), could identify fibrosis in selective areas of the myocardium, and to assess the relationship of the presence and extent of fibrosis to LV function.
Methods
The cardiology databases at Primary Children's Medical Center and Cincinnati Children's Hospital Medical Center were reviewed to identify patients with DMD who had undergone a CMRI within the last 2 years. Age, LV ejection fraction, LV mass, presence and location of LGE were documented. Volumes were measured using MASS (Medis, Inc.) to calculate ejection fraction and mass. LGE images were acquired and when positive, manual and customized computer assisted sizing of the areas of late gadolinium enhancement were performed on all slices. Normal function was defined as LV ejection fraction >54%.
Results
A total of 74 patients with DMD had complete data sets (median age 13.7 years, range 7.7 − 26.4). Twenty-four patients (32%) had LGE involving the posterobasal region of the LV in a sub-epicardial distribution. Those patients with more involvement had spread to the inferior and left lateral free wall with progressive transmural fibrous replacement. There was relative sparing of the interventricular septum and right ventricle. Patients with LGE were significantly older than those without (mean age16.4 years vs 12.9 years, p<0.001). LGE was positively associated with BSA-adjusted LV mass, LV end-diastolic volume, LV end-systolic volume, and RV end-systolic volume but inversely correlated with ejection fraction of the LV (p<0.001) and RV (p = 0.004).
Conclusions
LGE by CMRI is able to detect fibrosis in selective regions of myocardium in patients with DMD. Unfavorable LV remodeling, with a corresponding decreased ejection fraction, is associated with the presence of LGE. Serial studies are warranted to determine if LGE precedes a decrease in function, and if early medical management is useful in preventing progression once LGE is documented.
doi:10.1007/s10554-008-9352-y
PMCID: PMC2746925  PMID: 18686011
Duchenne muscular dystrophy; Magnetic Resonance Imaging; cardiomyopathy
20.  Three Cases of Manifesting Female Carriers in Patients with Duchenne Muscular Dystrophy 
Yonsei Medical Journal  2010;52(1):192-195.
Duchenne muscular dystrophy usually affects males. However, females are also affected in rare instances. Approximately 8% of female Duchenne muscular dystrophy (DMD) carriers are manifesting carriers and have muscle weakness to some extent. We investigated the clinical features of 3 female patients with dystrophinopathy diagnosed by clinical, pathological, and genetic studies at our neuromuscular disease clinic. The onset age of manifesting symptoms varied (8-28 years). Muscle weakness grade varied as follows: patient 1 showed asymmetrical bilateral proximal upper and lower extremities weakness, patient 2 showed asymmetrical bilateral upper extremities weakness similar to scapulohumoral muscular dystrophy, and patient 3 had only bilateral asymmetric proximal lower extremities weakness. Two patients had familial histories of DMD (their sons were diagnosed with DMD), but the 1 remaining patient had no familial history of DMD. The serum creatine kinase level was elevated in all patients, but it was not correlated with muscular weakness. An electromyography study showed findings of myopathy in all patients. One patient was diagnosed with a DMD carrier by a muscle biopsy with an immunohistochemical stain (dystrophin). The remaining 2 patients with familial history of DMD were diagnosed by multiplex ligation-dependent probe amplification (MLPA). There were inconsistent clinical features in the female carriers. An immunohistochemical analysis of dystrophin could be useful for female carrier patients. Also, multiplex ligation-dependent probe amplification is essential for the diagnosis of a manifesting female carrier DMD in female myopathic patients because conventional multiplex PCR could not detect the duplication and is less accurate compared to MLPA.
doi:10.3349/ymj.2011.52.1.192
PMCID: PMC3017697  PMID: 21155054
Dystrophinopathy; female carrier; multiplex ligation-dependent probe amplification
21.  Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location 
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70
doi:10.2478/bjmg-2014-0071
PMCID: PMC4413439  PMID: 25937795
Duchenne muscular dystrophy (DMD); dystrophin isoform; intellectual impairment
Gene therapy  2012;19(6):678-685.
The heart is frequently afflicted in muscular dystrophy. In severe cases, cardiac lesion may directly result in death. Over the years, pharmacological and/or surgical interventions have been the mainstay to alleviate cardiac symptoms in muscular dystrophy patients. Although these traditional modalities remain useful, the emerging field of gene therapy has now provided an unprecedented opportunity to transform our thinking/approach in the treatment of dystrophic heart disease. In fact, the premise is already in place for genetic correction. Gene mutations have been identified and animal models are available for several types of muscular dystrophy. Most importantly, innovative strategies have been developed to effectively deliver therapeutic genes to the heart. Dystrophin-deficient Duchenne cardiomyopathy is associated with Duchenne muscular dystrophy (DMD), the most common lethal muscular dystrophy. Considering its high incidence, there has been a considerable interest and significant input in the development of Duchenne cardiomyopathy gene therapy. Using Duchenne cardiomyopathy as an example, here we illustrate the struggles and successes experienced in the burgeoning field of dystrophic heart disease gene therapy. In light of abundant and highly promising data with the adeno-associated virus (AAV) vector, we have specially emphasized on AAV-mediated gene therapy. Besides DMD, we have also discussed gene therapy for treating cardiac diseases in other muscular dystrophies such as limb-girdle muscular dystrophy.
doi:10.1038/gt.2012.10
PMCID: PMC3628728  PMID: 22318092
muscular dystrophy; heart; cardiomyopathy; Duchenne muscular dystrophy; dystrophin; sarcoglycan
Background
Currently, there is no cure for Duchenne and Becker muscular dystrophies (DMD/BMD). However, clinical trials with new therapeutic strategies are being conducted or considered. A comprehensive database is critical for patient recruitment and efficacy evaluation. China has the largest population, yet, no comprehensive database for DMD/BMD is available. Our study registered the data of the DMD/BMD patients in East China.
Methods
A modified registry form of Remudy (http://www.remudy.jp/) was applied to Chinese DMD/BMD patients through the outpatient clinic at Children’s Hospital of Fudan University, Shanghai during the period of August 2011 to December 2013. The data included geographic distribution of patients, age at diagnosis, clinical manifestation, genetic analysis and treatment status.
Results
194 DMD and 35 BMD patients were registered. Most patients lived in East China, namely Jiangsu province, Anhui province, Zhejiang province, Jiangxi province, Shanghai, Fujian province and Shandong province. All individuals aged less than 18 years (age limit to a children’s hospital). Diagnosis was made for a majority of patients during the age of 3–4 (16.6%) and 7–8 (14.8%) years old. Exon deletion was the most frequent genetic mutations (65.5% and 74.3%) followed by point mutations (14.4% and 11.4%), duplications (9.8% and 8.6%) and small insertion/deletion (9.3% and 2.9%) for DMD and BMD, respectively. 82.5% of DMD registrants were ambulatory, and all the BMD registrants were able to walk. 26.3% of DMD registrants have been treated with steroids. Cardiac functions were examined for 46.4% DMD boys and 45.7% BMD boys and respiratory functions were examined for 18.6% DMD boys and 14.3% BMD boys. Four boys with abnormal cardiac function were prescribed for treatment with cardiac medicine. 33.2% of DMD patients are eligible for exon skipping therapy, and among them 9.2% and 4.3% patients are eligible for skipping exon 51 and 53, respectively.
Conclusions
The database is the first linking accurate genetic diagnosis with clinical manifestation and treatment status of dystrophinopathy patients in East China. It provides comprehensive information essential for further patient management, especially for promotion of international cooperation in developing experimental therapies such as exon skipping and read-through of nonsense mutations targeting a subgroup of DMD patient population.
doi:10.1186/s13023-014-0220-7
PMCID: PMC4323212  PMID: 25612904
Duchenne and Becker muscular dystrophy; The CHFU database; Patient management
Disability and rehabilitation  2014;36(22):1918-1923.
Purpose
While most studies of Duchenne muscular dystrophy (DMD) have focused on physical impairment, there is a need to explore how impairment impacts real life experiences in order to provide intervention strategies focused on participation. Objectives were: 1) to investigate the domains of participation in a sample of boys with Duchenne muscular dystrophy; 2) to compare a younger (<10 years) and older (≥10 years) group of boys with DMD with regard to participation; 3) to investigate strength and timed functional tests in a sample of boys with Duchenne muscular dystrophy; 4) to compare a younger (<10 years) and older (≥10 years) group of boys with DMD with regard to strength and timed functional tests; and 5) to explore associations between participation and strength and timed functional tests for our DMD cohorts.
Methods
This cross-sectional study included sixty boys with DMD (mean 9.3 years ±0.3). Boys completed strength testing, timed functional tests, the Children’s Assessment of Participation and Enjoyment and the ACTIVLIM. Independent samples t-tests were used to test for differences in all measures between our younger and older cohorts; Spearman’s (rank) correlation was used to assess relationships between participation and strength and time functional tests.
Results
Significant differences were found between our younger and older boys with DMD in the areas of recreational (p≤0.01), social (p≤0.001), and skill-based activities (p≤0.05), as well as with whom and where the activities were performed (p≤0.05 and 0.001, respectively). Older boys with DMD report lower levels of participation in these areas, as well as less engagement in activities with individuals other than family members and less participation outside of the home. Lower levels of strength and slower rates of functional performance correlate with participation in fewer physical activities for our younger cohort and fewer physical and social activities for our older cohort.
Conclusions
Strength and function relate to the variability and type of activities in which boys with DMD participate. A key finding is the significant decline in social activities and community-based engagement as the boys with DMD age. The ultimate goal of an intervention is for our children to be as actively engaged in life as they desire. This requires addressing participation when measuring outcomes in order to more fully understand limitations and provide appropriate strategies for continued participation for boys and their families.
doi:10.3109/09638288.2014.883444
PMCID: PMC4125555  PMID: 24499260
Duchenne muscular dystrophy; participation; strength outcomes; functional outcomes; social engagement
European Spine Journal  2012;22(2):411-416.
Purpose
Posterior instrumented spinal fusion is indicated for progressive scoliosis that develops in Duchenne muscular dystrophy (DMD) patients. Whilst spinal fusion is known to improve quality of life, there is inconsistency amongst the literature regarding its specific effect on respiratory function. Our objective was to determine the effect of scoliosis correction by posterior spinal fusion on respiratory function in a large cohort of patients with DMD. Patients with DMD undergoing posterior spinal fusion were compared to patients with DMD not undergoing surgical intervention.
Methods
An observational study of 65 patients with DMD associated scoliosis, born between 1961 and 2001: 28 of which underwent correction of scoliosis via posterior spinal fusion (Surgical Group) and 37 of which did not undergo surgical intervention (Non-Surgical Group). Pulmonary function was assessed using traditional spirometry. Comparisons were made between groups at set times, and by way of rates of change over time.
Results
There was no correlation between the level of respiratory dysfunction and the severity of scoliosis (as measured by Cobb angle) for the whole cohort. The Surgical Group had significantly worse respiratory function at a comparable age pre-operatively compared to the Non-Surgical Group, as measured by per cent predicted forced vital capacity (p = 0.02) on spirometry. The rate of decline of forced vital capacity and per cent predicted forced vital capacity was not slowed following surgery compared to the non-operated cases. There was no significant difference in survival between the two groups.
Conclusions
Severity of scoliosis was not a key determinant of respiratory dysfunction. Posterior spinal fusion did not reduce the rate of respiratory function decline. These two points suggest that intrinsic respiratory muscle weakness is the main determinant of decline in respiratory function in DMD.
doi:10.1007/s00586-012-2585-4
PMCID: PMC3555614  PMID: 23179984
Duchenne muscular dystrophy; Dystrophin; Respiratory function; Spirometry; Scoliosis; Surgical intervention

Results 1-25 (1302393)