In this thesis several studies are described that focused on the further unraveling of the epigenetic disease mechanism responsible for the development of FSHD. In chapter 2 a study is presented that made a detailed comparison between patients with FSHD and patients with ICF to determine whether there is an additional epigenetic, chromatin structure or clinical overlap besides the low DNA methylation on the first D4Z4 repeat. In chapter 3 a study is described that searched for a chromatin factor that differs between patients with FSHD and patients with ICF. Because this factor is only lowered in patients with FSHD (both in FSHD1 patients with less than 11 D4Z4 repeats and in FSHD2 patients with more than 10 D4Z4 repeats), but not in control individuals and in patients with ICF or in patients with another type of muscle disorder, it is concluded that indeed the chromatin structure of D4Z4 plays an important role in the development of FSHD. In chapter 4 a detailed DNA methylation study is described that tried to determine whether changes in chromatin structure explain the occurrence of FSHD only in individuals with less than 11 D4Z4 repeats on the 4qA161 variant of chromosome 4, while individuals with less than 11 D4Z4 repeats on the 4qA166 and 4qB163 variants and on chromosome 10 are healthy. Finally, in chapter 5 a pilot study is described in which we tried to change the chromatin structure of the D4Z4 repeat in patients with FSHD by folic acid supplementation.