Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle-wasting condition characterized by the progressive loss of muscle tissue, especially in the face, shoulder blades, and upper arms.

There are two types of FSHD, both caused by changes in a region of DNA near the end of the chromosome 4, known as the D4Z4 regionThe most common type, seen in 95 percent or patients, is called FSHD type 1 (FSHD1). The less common form, in the remaining 5 percent, is known as FSHD type 2 (FSHD2).

Healthy people

In healthy people, the entire D4Z4 region is hypermethylated, meaning it has a large number of methyl groups attached to the DNA. Methyl groups, formed by one carbon atom and three hydrogen atoms, turn off or silence genes. DUX4 is one such gene, found in the D4Z4 region, that is normally silenced. Its function is not completely known, but researchers think the DUX4 gene affects the activity of other genes, particularly in muscle cells.

People with facioscapulohumeral muscular dystrophy (FSHD)

FSHD results from hypomethylation — fewer methyl groups binding to DNA — of the D4Z4 region, resulting in an overactive DUX4 gene. How this overactivity damages or destroys muscle cells is not well-understood.

Hypomethylation of the D4Z4 region may be the result of two distinct genetic mechanisms; depending on the mechanism, a person will either have FSHD1 or FSHD2.

FSHD1

In FSHD1the D4Z4 region of chromosome 4 is shorter than normal, containing only 1 to 10 repeated DNA segments, instead of the usual 11 to 100. It is thought that this leads to fewer methyl groups being able to attach (bind) to the DNA, and hypomethylation.

FSHD1 is inherited in an autosomal dominant pattern, which means that a person only has to inherit one copy of chromosome 4 containing the shorter D4Z4 region to develop the disorder.

FSHD2

In FSHD2, hypomethylation occurs as a result of mutations in a gene called SMCHD1, which carries the instructions necessary to make a protein that hypermethylates the D4Z4 region. In the absence of functional SMCHD1 protein, that region becomes hypomethylated and the DUX4 gene active to excess. 

FSHD2 is inherited in a digenic pattern, which means that two independent genetic changes are necessary for disease development. These are a mutation in the SMCHD1 gene (on chromosome 18) and a so-called “permissive” chromosome 4, meaning it has a regulatory region that allows the DUX4 gene — silent in healthy people — to produce DUX4 protein. Often, people with FSHD2 inherit a mutated SMCHD1 gene from one healthy parent, and a  “permissive” chromosome 4 from the other. 

About 20 percent of FSHD2 patients, however, do not have an identified mutation in the SMCHD1 gene, and the cause of D4Z4 region hypomethylation is unknown.

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