What is FSHD?

What is FSHD?

Facioscapulohumeral muscular dystrophy [FSHD] is the third most common muscular dystrophy of humans. FSHD affects the facial muscles, shoulder girdles and upper arms, followed by weakness of the trunk and distal lower extremities in a later stage of the disease.

Two genetically distinct forms of FSHD occur. More than 95% of patients have FSHD type 1. Patients with this form of the disease have lost the D4Z4 repeated units on the long arm of chromosome 4 [4q35]. Healthy people have between 10-100 repeated units, and then the 4q35 region is silenced. Silenced means that genes in this area are not expressed]. In FSHD patients who have 1-10 units, there is no sufficient silencing and consequently expression of genes in this area are possible and the DUX4 gene is indeed expressed [the expression product is called DUX4 mRNA]. However only when also a polyadenylation sequence is present on this mRNA this mRNA is translated into DUX4 protein, which is the most likely causative agent of this disease. In more than 80 % of patients with FSHD2 hypomethylation is caused by a deletion in the SMCHD1 gene. This gene encodes a hypermethylation enzyme, but the mutant is less active and therefore hypomethylation occurs also of the D4Z4 region. The final result is as in FSHD 1, DUX4 protein is made resulting in cell death.

Other factors play a role in the progression rate of the disease. Oxygen radicals either formed by normal metabolic processes or during inflammation accelerates the disease just as it accelerates general ageing.

There is also a difference between women and men. For a long time this was not understood very well, but recently it has been found that estrogen – a female hormone – improves the differentiation of FSHD derived myoblast by antagonizing DUX4 activity.