Facioscapulohumeral muscular dystrophy [FSHD] is the third most common muscular dystrophy in humans. The disorder is characterised by the progressive weakening and waisting of skeletal muscle. The name FSHD reflects the muscles most often affected – the facial muscles, shoulder girdles and upper arms, but weakness of the trunk, hips and lower limbs also can occur especially in the later stages of the disorder. There can be considerable variation in the onset and severity of symptoms and there may be significant asymmetry in that muscles on one side of the body may be weaker than the other. Symptoms commonly become evident in adolescence but milder cases may not be noticeable until middle or even late adulthood whilst severe cases can present in infancy and childhood
Two forms of FSHD are generally distinguished, FSHD Type 1 and FSHD Type 2. The two types share the same symptoms, but they differ in their genetic cause. 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 silent (the technical term is methylated). Silenced means that genes in this area are not expressed. In FSHD1 patients who only have between 1-10 repeated units, there is insufficient silencing (called hypomethylation) and so expression of genes in this area is possible and the DUX4 gene is indeed expressed. The expression product is called DUX4 mRNA. However, only when a polyadenylation sequence is also present on this mRNA is this mRNA translated into DUX4 protein, which is the most likely causative agent of this disease leading to cell death. In more than 80 % of patients with FSHD Type 2 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 of the D4Z4 region also occurs. The final result is as in FSHD Type 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 oestrogen – a female hormone – improves the differentiation of FSHD derived myoblast by antagonizing DUX4 activity.