Longitudinal Study of the Natural History of Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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The purpose of this study is to establish the largest long-term assessment of people with Duchenne muscular dystrophy (DMD). In this study, the investigators associated with the Cooperative International Neuromuscular Research Group CINRG) will take a detailed look (for a minimum of eight years) at DMD participant's physical abilities, the medical problems they experience, and how they use health care services. Physical abilities will be compared to a group of healthy controls. The second purpose of this study is to find out whether small, normal differences in the genetic makeup of people with DMD (called single nucleotide polymorphisms or SNPs) affect how their disease progresses and relates to muscle strength/size and steroid response. The third purpose of this study is to study genetic variations associated with DMD. The final purpose of this study is to determine whether certain biomarkers are present in people with DMD and not in healthy controls.

Detailed Description
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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, and relative risks of developing those conditions based on exposure to preventive interventions. 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. Aim 7: Examine the associations between interventions and incidence and severity of secondary conditions, achievement of disease milestones and measures of motor function and mobility. Aim 8: To assess the validity and responsiveness of novel clinical outcome measures in DMD, including the 6-minute walk test (6MWT), the 9-hole peg test (9-HPT) Egen Klassification Scale(EK), the North Star Ambulatory Assessment (NSAA), and quantitative key and pinch grip strength testing. Aim 9: To assess the reliability, validity and responsiveness of novel patient-reported outcome(PRO) measures in DMD, including the NeuroQOL and PedsQL Neuromuscular Module. Aim 10: To assess the clinical meaningfulness of novel objective clinical outcome measures by assessing their ability to predict milestones of loss of ability to stand from supine, to stand from a seated position, to climb stairs, to ambulate independently and to raise a hand to the mouth. AIM 11: To determine the impact of development and growth on outcome measure performance,we will assess physical function on a group of healthy, typically developing male children and adults between 6 and 30 years of age for outcome measures of motor function and strength including the9-HPT, 6MWT, NSAA, timed function tests and quantitative muscle strength (QMT). Test results from this cohort will be used to develop initial percent predicted for age values for these assessments. SNP Genotyping Study Aim Our goal of 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 (>1%) 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. Genome-wide Association Study Aim Our goal of the proposed study is to isolate genomic DNA and find possible correlations of clinical phenotypes with gene loci associated with mild vs. severe clinical presentation, progression, or response to steroids. Serum Biomarkers Study Aim Our goal is to discover and validate sensitive and specific serum biomarkers for DMD.

Official Title
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Longitudinal Study of the Relationship Between Impairment, Activity Limitation, Participation and Quality of Life in Persons With Confirmed Duchenne Muscular Dystrophy (DMD)

Conditions
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Duchenne Muscular Dystrophy

Participation Criteria
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Eligibility Criteria
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DMD Subject Inclusion Criteria Affected subjects must be male and between the ages of 2 and 30 Affected subjects between the ages of 2 and 4 must have a diagnosis of DMD confirmed by at least one the following OR have an older male sibling that meet at least one of the following criteria: Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical Duchenne dystrophy OR Gene deletion test positive (missing one or more exons) in the central rod domain exons 25-60) of dystrophin, where reading frame can be predicted as 'out-of-frame',and clinical picture consistent with typical Duchenne dystrophy. Complete dystrophin gene sequencing showing an alteration (point mutation, duplication, other) that is expected to preclude production of the dystrophin protein(i.e. nonsense mutation, deletion/duplication leading to a downstream stop codon),with a typical clinical picture of DMD. Affected subjects between the ages of 5 and 30 must either fulfill the above criteria OR show evidence of a dystrophinopathy and clinical picture consistent with Duchenne Muscular Dystrophy Participants who have documented clinical symptoms referable to a dystrophinopathy and direct support of the diagnosis by either (1) a positive DNA analysis for dystrophin mutation, (2) a muscle biopsy demonstrating abnormal dystrophin, or (3) an elevated CK (>5X normal), and X-linked pedigree and an affected family member who meets either criterion (1) or (2) as described above. NOTE: Determination of the appropriate clinical symptoms consistent with DMD will generally be the responsibility of the clinician. At a minimum this will include progressive loss of function, with additional consideration for other clinical features such as a characteristic gait, a positive Gower sign and calf pseudohypertrophy. When immunostaining of muscle biopsy is used to determining case definition, the clinical reviewer (site PI) should confirm that appropriate testing has ruled out a secondary deficiency of dystrophin. Affected subjects that do not exhibit the above symptoms consistent with DMD should be excluded. o Muscle weakness prevalent by 5 years of age - Non-affected adult subjects must be Parent(s) or legal guardian(s) of an eligible affected subject. DMD Serum Biomarker Inclusion Criteria Participants must meet eligibility criteria for the DMD phenotyping portion of this study For the GC-treatment response cohort, participants must initiate GC treatment within the first year of study participation (i.e. between their first study visit and their one year follow-up visit) DMD Subject Exclusion Criteria For those subjects that confirm DMD diagnosis through a clinical picture consistent with DMD Steroid-naïve subjects ambulating past the 13th birthday Steroid users ambulating past the 16th birthday Subjects/families who are unwilling or unable to comply with the protocol study procedures or visits Controls Subject Inclusion Criteria Male sex Age 6-30 years Able to comply with functional testing instructions Control Serum Biomarker Inclusion criteria Participants must be male Participants must be free of DMD, other neuromuscular disease, or other significant concomitant illness Participant must be free of glucocorticoid therapy Control Subject Exclusion Criteria Musculoskeletal disease Musculoskeletal injury within 6 months of enrollment Other concomitant illness that precludes functional testing in the judgment of the investigator or clinical evaluator Completion of enrollment for age cohort

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ongoing Duchenne Muscular Dystrophy (DMD) Cohort<br>340 patients currently enrolled participants with DMD. | |
| New Young Duchenne Muscular Dystrophy (DMD) Cohort<br>Additional 100 confirmed DMD participants aged 4-7 years old to be recruited. | |
| Typically Developing Control Cohort<br>Up to 370 typically developing male children and adults aged 6-30 years old to be recruited. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Strength and function | These assessments include: Quantitative muscle testing Manual muscle testing Pulmonary function testing Functional evaluations (nine hole peg, six minute walk, North Star ambulatory assessment, Brooke and Vignos scales, Egen Klassification (EK) scale, and range of motion). | Collected at yearly visits | 
| Quality of life | These questionnaires include: Pediatric Quality of Life Inventory (PedsQL) Pediatric Orthopaedic Functional Health Questionnaire of the Pediatric Orthopaedic Society of North America (POSNA) World Health Organization Quality of Life Assessment - Brief (WHO QOL Brief) Pediatrics and Adult Neuromuscular module Quality of Life (NeuroQOL) Review of Systems | Collected at yearly visits | 
| Medical history assessment | Outcomes on ambulation status, medication history, hospitalizations, surgeries, nutrition, fractures, and cardiac tests. | Collected at yearly visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers and genetic modifiers | Genotyping and Serum Biomarkers include blood/saliva collection for: Blood collection for Genome Wide Association Study (GWAS) analysis (one time sample, any visit) Blood or saliva collection for SNP sample (one time sample, any visit) Blood collection for biomarker analysis (collected at each visit) | Collected either once at any visit or each visit |