This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study will establish the largest comprehensive longitudinal assessment of individuals with Duchenne muscular dystrophy, and it will be the first that uses the World Health Organization's new framework on the International Classification of Functioning, Health and Disability. It will also longitudinally assess the psychosocial impact of the disease as it progresses on the affected persons with DMD and their families. The study will longitudinally examine the relationship between impairment, secondary conditions, activity limitation, participation and quality of life. In addition the study will evaluate the psychosocial impact of DMD in a large cohort of subjects. Regression analyses will determine the modifying effects of impairment, activities, participation and demographic data on quality of life. Successful development of an extensive and broad database will allow the performance of longitudinal prospective rehabilitation research, and evaluation of broad interventions in relation to quality of life outcomes in neuromuscular disorders. Also, the study will investigate single nucleotide polymorphisms (SNPs)in DMD patients to see how genetic variability potentially influences the efficacy of corticosteroid treatment in DMD. In addition, this project will provide a model for future multicenter efforts focusing on rehabilitation research for other neuromuscular diseases. Outcomes of this work will reach males with DMD and their families and may impact future public health policies that will positively affect their quality of life. HYPOTHESIS: Long term assessment of patients with DMD will reveal new physical and psychosocial characteristics related to the progression of the disease that will aid in diagnosis and treatment and facilitate improvements in patient quality of life. Also, analysis of genetic variability among DMD patients will provide new information related to improving DMD therapy.
SPECIFIC AIMS : Phenotyping Study Aims Aim 1: Longitudinally assess body function and body structure (impairment) through the measurement of anthropometrics, muscle strength and pulmonary function in subjects with DMD through the multicenter CINRG network.
Aim 2 : Longitudinally assess activity limitations in subjects with DMD through CINRG with timed motor performance, burden of care, and functional status.
Aim 3 : Longitudinally assess secondary conditions in subjects with DMD.
Aim 4 : Longitudinally assess participation, life satisfaction, service utilization and health-related quality of life in subjects with DMD.
Aim 5 : Determine appropriate outcome measurements for impairment, activities (activity limitations), participation and quality of life to determine the effect of prednisone and other therapeutic interventions on these factors.
Aim 6 : Using the most robust impairment, activity, participation and quality of life outcome measures, determine the sample size, power and statistical methods for the analysis of the effect size for future planned randomized-controlled rehabilitation interventions in DMD. SNP Genotyping Study Aims Our goal of this the proposed study is to define polygenic modifiers of disease progression, and also response to treatment with glucocorticoids (prednisone and deflazacort). The most common type of human genetic variation is the single-nucleotide polymorphism (SNP) a base position at which two alternative bases occur at an appreciable frequency (gt);in the population. SNPs are 90% of variation in the human genome. SNPs occur on the average of 1 per 1000 to 2000 bp throughout the 3.2 billion bp of the human genome while coding region SNPs (cSNPs) occur on the average of 1 per 346 bp. BACKGROUND AND SIGNIFICANCE: Duchenne muscular dystrophy (DMD) is an X-linked developmental disorder that causes progressive muscular weakness usually leading to death by young adulthood. DMD occurs with an incidence of about 30 per 100,000 live born males across all ethnic groups studied. Although a majority of cases of DMD are inherited, about one third of DMD cases are the result of spontaneous mutations. DMD is the most common NMD of childhood and has been shown to be the neuromuscular disorder requiring the greatest annual per capita cost for outpatient rehabilitative treatment. Even though phenomenal advances have been made in the understanding of the molecular genetics of DMD, no cure has been found. The combination of the disease's prevalence, seriousness, unpredictable occurrence, cross-cultural presentation, and the combined emotional and financial expense of the clinical sequelae make DMD a significant public health concern. In DMD, the course of the physical impairment is progressive. Early motor developmental milestones tend to be delayed, and by age four or five, falling and/or trouble climbing stairs becomes increasingly apparent. As muscles continue to weaken, the boys begin to walk stiffly with lumbar lordosis to compensate for weakening leg muscles, and they require increased physical support. Mean age to the initial use of a wheelchair is 10 years with a range of 7 to 13 years. Death generally occurs by early adulthood, mostly due to respiratory or cardiac failure resulting from extreme muscle weakness. The last comprehensive evaluation of the natural history of Duchenne muscular dystrophy occurred in the 1980s under the direction of the Clinical Investigations in Duchenne Dystrophy (CIDD) group. It is considered a seminal study of individuals with disease, and is routinely cited in the development of clinical trials in DMD. However, the study occurred in the pre-molecular diagnostics and pre-prednisone eras. Recent clinical trials suggest that estimates of strength loss / disease progression in DMD no longer hold true, possibly due to inclusion of non-Duchenne individuals in the original study sets, or due to improvements in clinical care of individuals with DMD in the past 15 to 20 years. Because of these issues, it is necessary for us to conduct another long-term comprehensive review of the normal clinical course of DMD in the context of current clinical care paradigms. This study will establish the largest comprehensive longitudinal assessment of individuals with Duchenne muscular dystrophy, and it will be the first that uses the World Health Organization's new framework of the International Classification of Functioning, Health and Disability. It will also longitudinally assess the psychosocial impact of the disease as it progresses on the affected persons with NMD and their families. In addition to redefining the natural history of the disease, this study will also seek to determine whether the presence of normal genetic variations (SNPs) that have been associated with both steroid response and muscle hypertrophy can affect the treatment outcome of individuals who receive corticosteroids to improve their strength and respiratory function. The Cooperative International Neuromuscular Research Group (CINRG) has developed the first multicenter clinical trial system for DMD since the dissolution of the MDA-funded Clinical Investigation of Duchenne Dystrophy over 10 years ago. In current clinical pharmacologic studies the outcome measurements for the study of pharmacological interventions in humans have been limited to measurements of impairment via manual muscle tests, as primary outcome measures. Secondary outcome measures have typically been limited to quantitative muscle tests, pulmonary function tests, and timed motor performance tests. Activity limitations, participation, secondary conditions, and quality of life issues have not been documented or addressed longitudinally in Duchenne muscular dystrophy in a collaborative effort. The lack of such outcome data precludes the understanding of the longer-term effects of effective drugs, such as prednisone. DMD, which is both chronic and terminal, may be characterized as a "complex chronic condition"in that it involves specialized and time-consuming care, even when the terminal phase lies years in the future. As such, it may be expected to have effects on the family similar to those observed in other chronic and terminal illnesses. With a diagnosis of DMD, many psychological adjustments become necessary. Further, DMD poses stressors in terms of daily care requirements, such as hygiene and other self-care skills, negotiating wheelchair transportation, and meeting recommended physical therapy requirements. Research examining families with chronically ill children indicates that multiple factors contribute to the degree of distress the families feel and how well they cope. Coping is influenced by both the actual demands of the situation and the resources that are available. Resources may be material or financial, physical (health and fitness), psychological, (values, attitudes, beliefs)or social (family and community support). Accordingly, in order to study the impact of DMD on a family, many variables must be examined. Determination of what services are available and what services are used within the context of treatment for DMD, as well as what the affected individuals perceive their benefit to be, is necessary to determine where health care modifications may have their greatest benefit for families living with DMD. Little research has been done to examine service utilization and need specifically in families affected with DMD. From a public health perspective this is surprising, given the complex needs and costs incurred by the DMD population. Review of annual per capita costs in an outpatient neuromuscular rehabilitation clinic demonstrated that treatment for individuals with DMD was substantially more expensive than treatment for the other neuromuscular disorders. In a recent survey of 31 affected families, families reported that physiotherapy, genetics and research into treatment for the disorder were very important, and psychologic and psychiatric services were much less important, yet they did not address whether the families felt these services were adequately provided. In a survey of 32 patients with DMD and their parents, the need for life expectancy information and counseling was rated as important, yet unavailable. Psychosocial impacts of the disease severity and service utilization have been studied in many childhood chronic disorders;there is limited information available on their consequences in DMD. Although the primary genetic defect in DMD, which causes virtual absence of dystrophin, cannot currently be corrected, the disease is not untreatable. A host of pharmacological, rehabilitation and psychosocial management techniques are being used to help the affected children and their families. Efforts are focused upon improving quality of life and delaying the course of the disease. The clinical onset and the rate of progression of DMD and the other genetic neuromuscular disorders are modifiable. The goals of treatment are to slow disease progression, control secondary conditions and to improve the quality of life of the patients and families living with the disease. Today treatment across the United States varies geographically, but more frequently includes a continuous course of corticosteroid therapy and more and more centers in the U.S. use this as standard of practice, although the age of initial use and duration of therapy vary widely. Daily therapy, a set of exercises overseen and performed by the primary caregiver, and monitored closely by a physical therapist, is also prescribed to maintain optimal muscle function. In many instances, surgery is performed during childhood to elongate tendons in the leg, and, after several years of wheelchair use, surgery may be performed to correct spine curvature that negatively impacts pulmonary function. Later in the progression of the disease (usually in the late teens) assisted mechanical ventilation can become necessary to prolong life. There is mounting evidence that the weakness and disability characteristics of the muscular dystrophies are not an immediate consequence of a single biochemical defect, but are due to disruption of a series of downstream pathological pathways that gradually lead to muscle wasting and infiltration of the muscle with fatty and connective tissue. Pharmacological, nutritional and physical interventions are being proposed to modify disease pathophysiology that affects the onset and progression of the disease. Over two-dozen drugs, proteins and nutritional compounds have been shown to slow the progress of the dystrophic process in the mdx mouse and the dystrophic chicken. Of these drugs, corticosteroids such as prednisone and deflazacort have been shown to be the most effective in slowing the progression of Duchenne dystrophy. Unfortunately, their long-term use has been limited because of their significant side effects. To minimize the side effects, CINRG is currently performing a randomized-controlled trial that administers corticosteroids with a pulse therapy technique instead of daily administration. To date, the only proven effective palliative therapy for DMD has been the treatment with corticosteroids. Well- designed double-blinded randomized controlled trials have shown that prednisone, deflazacort and oxandrolone provide significant functional improvement in boys with DMD. Over 12 randomized controlled trials on nearly 1000 affected children with DMD have shown that steroids have provided transitory improvement and/or stabilization of muscle strength during trials lasting up to six months. However, the long-term use of corticosteroids has been problematic because these drugs have significant systemic side effects. These side effects include excessive weight gain, hirsuitism, acne, stria, hypertension, cataracts, osteoporosis, increased anger, increased anxiety and increased potential for steroid-induced cardiomyopathy. Connolly reported that more than 50% of boys with DMD treated with daily corticosteroids discontinue their treatment due to excessive weight gain, cushinoid faces and behavioral changes. After many years of treatment, the dose of prednisone is often reduced because of the systemic steroid side effects. In his review of clinical trials in Duchenne muscular dystrophy, Francesco Muntoni emphasized that the lack of the widespread use of steroids was """"""""due to the lack of functional outcome and quality of life measures in most published studies."""""""" In his address to the 2002 MDA national Clinic Directors Meeting, Dr. John Kissel, MDA clinic co-director at Ohio State University, echoed the need for increased studies regarding the quality of life of individuals with Duchenne muscular dystrophy to evaluate the effectiveness of pharmacological and physical interventions. This project will provide the information that will fill these needs and a framework for outcomes measurement, which ultimately can be applied to other NMD conditions While glucocorticoids clearly have a strong effect on skeletal muscle in normal individuals, glucocorticoids are the only drugs shown to have a significant positive effect on both strength and function in boys with Duchenne muscular dystrophy (DMD). When considering the various matabolic effects exerted by glucocorticoids, it appears almost paradoxical that they would improve dystrophic muscle strength and function. These catabolic effects indeed result in muscle weakness and atrophy in normal human muscle, a decrease in protein synthesis and increased protein degradation. In patients with DMD however, there is an overall positive effect;this has traditionally been attributed to the anti-inflammatory action and increased myoblast proliferation and fusion, although none of these mechanisms seem to explain the relatively rapid improvement in strength seen in DMD boys. Extensive studies of corticosteroids on dystrophin-deficient muscle in vivo and in culture have demonstrated an immunosuppressive effect, including an effect on dendritic cells, and a decrease in intracellular calcium ion concentrations. Additional putative mechanisms of action include a stabilization of muscle fiber membranes, followed by reduction in muscle necrosis. These, and other less characterized effects, appear to contribute to the observed increased muscle mass of prednisone-treated DMD patients. Even if steroids are effective in DMD, interpatient variability in steroid response and severity of side-effects are well known. Data derived from analysis of the standard deviation in several reports in the literature often show standard deviations greater than the mean, suggesting a broad distribution of values presumably due to the existence of patients performing either extremely well or poorly. Moreover, wide variation in the age at which loss of ambulation occurs among steroid-treated DMD patients is also reported. This project focuses on responsiveness to corticosteroids, and genetic underpinnings of the variable response. Steroid therapy, however helpful, is certainly not benign and not without adverse effects. Furthermore, some DMD patients do not respond favorably to steroids and develop significant side effects effects like hypertension, osteoporosis and glucose intolerance, and behavioral changes to name a few. Data from past studies of DMD patients on steroids has shown standard deviations greater than mean for both strength and age at the time of loss of ambulation, indicating that response to steroids is by no means uniform and the same can be said about the propensity to develop adverse effects. The variation in clinical response to steroids is likely driven by underlying genetic polymorphisms (SNPs) that vary from individual to individual.
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