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Update by Dr. Kathryn Wagner.
This is a proposal to study the histopathological features of muscle in a large biobank from FSHD patients and their first degree family members. By establishing a detailed morphometric signature of FSHD, we will be able to develop muscle pathology as an outcome measure in future clinical trials. In our cohort of 75 biopsies, we identify significant differences between the morphological and histopathological features in FSHD vs. Control biopsies. Specifically, FSHD muscle compared to control exhibits a significant increase in percentage of atrophic, necrotic and regenerating myofibers. The percentage of cells with internalized nuclei and percentage area of fibrosis is also significantly increased in FSHD. Contrary to previous descriptions, our results do not demonstrate that there is an increase in split myofibers in FSHD compared to controls. Further examination of biopsies in this cohort demonstrates that FSHD muscle has a significantly increased frequency of larger myofibers compared to controls, and this is particularly true for type IIa and IIx myofibers. Our future analysis will be aimed at trying to better understand different factors influencing these differences: age, gender, genetic testing results, and muscle function. Further, by correlating specific features such as degeneration and inflammation with DUX4 expression, we will be able to determine whether DUX4 has a primary or secondary effect on muscle pathology.