Facioscapulohumeral Muscular Dystrophy (FSH, FSHD)

Causes/Inheritance

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited neuromuscular disorder that causes weakness most prominently of the muscles in the face, shoulder blades, and upper arms. It often progresses to cause widespread muscle weakness, and it can also cause loss of hearing.

The region of human chromosomes that causes FSHD contains a section with multiple identical units of DNA called D4Z4 repeats. The number of D4Z4 repeat units in the general population varies from 11 to 100. Each repeat contains a copy of a gene called DUX4. This gene is used during fetal development, but in adulthood, the DNA in this region is normally “condensed,” or packed tightly together, which prevents the cellular machinery from reading the DUX4 gene. As a result, no protein is made from it once fetal development is completed.

In approximately 95% of patients with FSHD, the D4Z4 allele is contracted, meaning that multiple D4Z4 units are lost. This de-condenses the DNA and reactivates the DUX4 gene, allowing aberrant production of the DUX4 protein. Synthesis of DUX4 transcripts and protein is toxic in muscle cells. In most patients with FSHD, one D4Z4 allele (a variant form of a gene) is contracted to between 1 and 10 repeat units and the other D4Z4 allele has the normal number, a condition termed FSHD1.

There is an inverse relationship between the onset and clinical severity of FSHD, and the size of the pathogenic (contracted) D4Z4 repeat units. Individuals with one to three repeat D4Z4 units are typically at the severe end of the disease spectrum. With four to 10 repeat units, the clinical variation ranges from asymptomatic to severely affected. An allele with 10 to 11 D4Z4 repeats is considered borderline. Many FSHD researchers now believe that elevation of DUX4 protein causes the symptoms of FSHD.

In less than 5% of people with FSHD, the D4Z4 region is of normal length, a condition termed FSHD2. In these individuals, mutations in a different gene, called SMCHD1, cause the DNA in the vicinity of the D4Z4 repeats to be spread out, allowing the DUX4 gene to be read and protein to be produced.

A mutation from one parent is sufficient to cause FSHD

FSHD1 is inherited in an autosomal dominant pattern, meaning it takes only one mutation (from one parent) to cause the disorder. This altered piece of DNA also can occur spontaneously in a child as he or she develops in the womb, which accounts for 10% to 30% of FSHD1 cases. The inheritance of FSHD2 is not fully established and in most cases may require mutations in SMCHD1 on chromosome 18. Approximately 60% of FSHD2 cases appear to be sporadic.

For help in understanding your family’s specific situation and planning for future children, it is best to meet with a genetic counselor.