The overall goal of this natural history study is to define the key LGMD2i phenotypes as measured by standard clinical outcome assessments (COAs), and to validate a muscle biomarker for LGMD 2i to support therapeutic development.
Limb Girdle Muscular Dystrophy (LGMD) 2i is an autosomal recessive form of LGMD that is due to missense mutations in the FKRP gene. Patients develop progressive proximal muscle weakness that leads to loss of ambulation. Patients will also commonly develop a cardiomyopathy and respiratory compromise.
There are promising new therapies that have been developed and as a result therapeutic trials are approaching.
The rationale for this study is to define appropriate COAs for LGMD 2i, which will facilitate therapeutic development and ensure properly powered clinical trials. In addition, measurement of dystroglycan in muscles represents a potential muscle biomarker that could be used in early phase clinical trials as a measure of target engagement. The clinical utility of changes in dystroglycan has not been validated in human samples.
1. 10-Meter walk -mobility [ Time Frame: Through study completion at 12 months ]
Participants will complete three trials of the 10-meter walk test. The fastest time will be recorded, in addition to the average of the three trials. The test will be conducted in a quiet hallway and the participant will be instructed to walk their normal self-selected pace from one cone to the next along the 10-meter course marked on the floor. No assistive devices or flip-flops are allowed, and the test will be performed either barefoot or in well-fitting shoes. Orthoses and ankle braces will be allowed. The Time Frame provided is not specific. The Time Frame should indicate the specific time point(s) at which the outcome measure will be assessed and for which data will be reported. Examples: "baseline" "1 year" "up to 24 weeks" "through study completion, an average of 1 year".
2. 100-Meter lap - mobility [ Time Frame: Through study completion at 12 months ]
- The participant will be asked to complete 2 laps around 2 cones set 25 meters apart as quickly as safely possible, running if able and the time in seconds is recorded. This will not be assessed in participants with a 10-meter walk time greater than 12 seconds.
3. NSAD- Motor performance [ Time Frame: Through study completion at 12 months ]
- North Star Assessment for Dysferlinopathy (NSAD) is a functional scale specifically designed to measure motor performance in individuals with LGMD. It consists of 29 items that are considered clinically relevant items from the North Star Ambulatory Assessment and the Motor Function Measure 20 with a maximum score of 54 and higher scores indicate higher functional abilities.
4. Timed up-and-go (TUG) - mobility [ Time Frame: Through study completion at 12 months ]
- The TUG will be administered using the appropriate stable seating surface (i.e., cube chair or straight back chair) to achieve 90 degree of both hip and knee flexion when participant is seated with both feet flat on the floor to start. No flip flops will be allowed, and the test should be performed either barefoot or will well-fitting shoes on. Assistive devices, orthoses and ankle braces will be allowed.
5. FVC - Pulmonary function [ Time Frame: Through study completion at 12 months ]
- The total amount of air exhaled during the forced expiratory volume test (Forced vital capacity - FVC) will be assessed in a supine position.
6. 4 stair Climb - mobility [ Time Frame: Through study completion at 12 months ]
- Participants will perform the 4-stair climb with instructions to ascend 4 steps as quickly as safely possible using handrails if needed. The time to ascend the 4 steps will be recorded. This will not be assessed in participants with a 10 meter walk time greater than 12 seconds.
7. 9 Hole Peg Test - distal upper extremity function [ Time Frame: Through study completion at 12 months]
- The 9HPT is a quantitative measure of distal upper extremity function. It measures the ti me required for patients to place 9 pegs in the 9 holes on the board and then remove them as quickly as possible. The total time to complete the task is recorded.
8. Performance of Upper Limb (PUL 2.0) - limb function [ Time Frame: Through study completion at 12 months ]
- The PUL is a tool designed for assessing upper limb function in persons with neuromuscular disorders.39 It was developed as a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. There are 22scored items; a score of 42 indicates the highest level of independent function and 0 the lowest.
9. Hand Held Dynamometry (HHD) and Pinch Grip - isometric strength [ Time Frame: Through study completion at 12 months ]
- Hand held dynamometry using the MicroFET2 myometer will be utilized to capture isometric stre ngth in target muscle groups. Maximum strength in kilograms will be reported for each muscle gr oup provided a continuous scale variable for analysis.
1. To develop clinical outcome assessments for LGMD2i [ Time Frame: Through study completion at 12 months ]
- To determine the sensitivity of the COAs to longitudinal disease progression
Ages Eligible for Study: 10 Years to 65 Years (Child, Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sampling Method: Probability Sample
- Age between 10-65 at enrollment
- Clinically affected (defined as weakness on bedside evaluation in either a limb-girdle pattern, or in a distal extremity)
- A genetically confirmed mutation in FKRP (LGMD 2i).
- Up to 60 participants will complete the10-meter walk test in greater than 4 seconds.
- Up to 40 participants will complete the 10-meter walk test in over 12 seconds.
- Up to 20 participants may be non-ambulatory
- Any other illness that would interfere with the ability to undergo safe testing or would interfere with interpretation of the results in the opinion of the site investigator.
- History of a bleeding disorder, platelet count <50,000, current use of an anticoagulant.
- Positive pregnancy test at time any timepoint during the trial
United States, California - University of California Irvine - Irvine, California, United States, 92697
United States, Colorado - UC Denver - Aurora, Colorado, United States, 80045
United States, Florida - University of Florida - Gainesville, Florida, United States, 32610
United States, Iowa - University of Iowa - Iowa City, Iowa, United States, 52242
United States, Kansas - Kansas University Medical Center - Kansas City, Kansas, United States, 66160
United States, Maryland - Kennedy Krieger Institute - Baltimore, Maryland, United States, 21205
United States, Massachusetts - Brigham and Women's - Boston, Massachusetts, United States, 02035
United States, Missouri - Washington University School of Medicine - Saint Louis, Missouri, United States, 63110
United States, North Carolina - Atrium Health - Charlotte, North Carolina, United States, 28207
United States, Ohio - Nationwide Children's Hospital - Columbus, Ohio, United States, 43205
United States, Virginia - Virginia Commonwealth University - Richmond, Virginia, United States, 23298
Denmark - Copenhagen Neuromuscular Center - Copenhagen, Denmark
Virginia Commonwealth University
ML Bio Solutions
Nicholas E Johnson, MD
Virginia Commonwealth University