EVALUATION OF LIMB-GIRDLE MUSCULAR DYSTROPHY

Children'S Research Institute, Washington DC

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Abstract

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. Limb-girdle muscular dystrophy (LGMD) is largely a descriptive term for a molecularly heterogeneous group of muscular dystrophies with onset in childhood or adulthood that is characterized by muscle weakness. The weakness affects primarily the proximal limb musculature more than the distal limb musculature, relatively sparing the facial and bulbar musculature, and cardiac muscle is only occasionally affected. LGMD are classified into two large groups based on the mode of inheritance, type 1 for autosomal dominant and type 2 for autosomal recessive. Each type is further subdivided depending on the molecular etiology, designated by a letter in the order they were discovered. The study aims include: Aim 1: Evaluate integrity of the extracellular matrix in patients with LGMD by measuring serum growth factors and cytokines and compare these to a disease control (BMD) and normal volunteers. Aim 2: Measure growth factors and cytokines following medical evaluation and compare them to the baseline levels. Aim 3: Discovery Aim for future multicenter clinical trials in LGMD. Aim 3A: Abstract medical records with particular emphasis on age of disease onset, initial clinical symptoms, progression and location of the muscular weakness, treatments attempted, and other medical complications. A review of the diagnostic testing performed will also be conducted. Aim 3B: Perform complete clinical evaluation including amperometric measures, evaluation of joint limitations, timed functional testing, muscle strength, pulmonary function, and a cardiac assessment. Aim 3C: Determine patient understanding of diagnosis of LGMD and genetic testing results. A questionnaire will be generated that addresses the patient's understanding of his/her diagnosis as well as their understanding of genetic concepts of autosomal recessive inheritance, genes, molecular testing and implications for themselves as well as their family. Aim 3D: Quality of Life (QOL) questionnaires will be administered. These will be used to identify functional limitations by the patients and compare those limitations with the clinical evaluation. Individuals interested in participating will be asked to come to the Pediatric Clinical Research Center at Children's National Medical Center to complete the informed consent process and have blood drawn. A history and physical exam will be done on the patients at this time. All control participants will be normal healthy volunteers without any form of muscular dystrophy. Control subjects will be required to come to the Pediatric Clinical Research Center at Children's National Medical Center to complete the informed consent process and have blood drawn. Manual muscle testing and cQMS will be performed to assess differences in serum enzymes, growth factors, and cytokines. No other examinations or procedures will be performed on the control participants. Only one visit to CNMC will be necessary for both subjects and controls. 1. Medical Clearance 2. Medical history review will be conducted in regards to age of onset, clinical symptoms, other organ system involvement, treatments tried and responses, and diagnostic workup. 3. Physical Evaluation utilizing CINRG Quantitative Measurement System (CQMS) will be performed during the visit. Testing will take approximately an hour to an hour and a half, and should occur prior to the physician's visit. Physical evaluation utilizing CQMS testing will include: Manual Muscle Testing, Quantitative muscle testing, Pulmonary function testing, Anthropometric measurements, and Timed and Functional testing 4. Cardiac evaluation including physical exam, electrocardiogram, echocardiogram and electrocardiogram will be performed on the patients by an attending cardiologist in the outpatient cardiology clinic. 5. Blood collection: Blood will be collected for the following: i) DNA extraction to confirm genotype will be performed only if you were diagnosed at the CNMC genetic lab and your diagnosis was based on muscle biopsy and not on molecular testing ii) Serum for muscle enzymes to be done clinically before and after the evaluation. iii) Serum for growth factors and cytokines before and after the evaluation. 6. Phone call follow up