Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD)

GRASP-LGMD: Defining Clinical Endpoints in LGMD

Limb Girdle Muscular Dystrophy comprise a group of disorders made up of over 30 mutations which share a common phenotype of progressive weakness of the shoulder and hip girdle muscles. While the individual genetic mutations are rare, as a cohort, LGMDs are one of the four most common muscular dystrophies. The overall goal of project 1 is to define the key phenotypes as measured by standard clinical outcome assessments (COAs) for limb girdle muscular dystrophies (LGMD) to hasten therapeutic development.

The genetic heterogeneity has been a barrier to broad natural history efforts, with prior investigations often limited to single gene mutations. Much attention is paid to the variability within individual mutations (e.g. distal presentations), as opposed to defining the best strategy for measuring change in overall LGMD disease burden. This presents a major dilemma for LGMD rare disease research: how to balance diverse genes leading to overlapping phenotypes, versus variants in the same gene leading to divergent phenotypes. What is clear, is as a group, LGMDs are chronic and progressive leading to significant lifetime morbidity and represent a large unmet clinical need.

Recent developments in the investigator's genetic understanding of LGMD and molecular approaches to therapy have led to proposed gene replacement therapies for at least three of the LGMD mutations. Several of these gene replacement therapies are currently in pre-clinical/phase 1 testing, leading to an urgent need for natural history data. In addition, non-specific therapies which target muscle mass or function are being tested in other muscular dystrophies and may prove beneficial for LGMD.

Inclusion Criteria - Arm 1:

• Age between 4-65 at enrollment
• Clinically affected (defined as weakness on bedside evaluation in either a limb-girdle pattern, or in a distal extremity)
• A genetically or functionally confirmed mutation in ANO5, CAPN3, DYSF, DNAJB6 or SGCA-G.
• Willing and able to give informed consent and follow all study procedures and requirements

Inclusion Criteria - Arm 2:

• Age between 4-65 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 SGCA-G
• Willing and able to give informed consent and follow all study procedures and requirements

Exclusion Criteria - Arm 1:

• 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.

Exclusion Criteria - Arm 2:

• 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.