What Is Facioscapulohumeral Muscular Dystrophy (FSHD)?

Facioscapulohumeral muscular dystrophy — sometimes abbreviated as FMD, FSH, or FSHD — is a form of muscular dystrophy that affects roughly one out of every 8,000 people, or about 870,000 people worldwide.

The disease gets its name because it characteristically affects muscles of the face (“facio”), the shoulders (“scapulo,” referring to the shoulder blade or scapula), and upper arms (“humeral,” referring to the humerus, the uppermost bone in the arm that connects shoulder to elbow).

Causes

Near the end of chromosome 4, there is a section of DNA called the D4Z4 region. This region consists of a sequence that is roughly 3,300 DNA base pairs (“letters”) long, and gets repeated over and over again — most people have anywhere from 11 to more than 100 repeats in the D4Z4 region. One of the genes located in D4Z4 is called DUX4, and it provides instructions for making a protein of the same name.

Normally, the entire D4Z4 region is “silenced” through a process called hypermethylation — essentially, chemical modifications are made to the DNA molecule, which “turns off” the section of DNA. This means that, most of the time, cells do not make any DUX4 protein, since the DUX4 gene is “turned off” along with the rest of the D4Z4 region. However, DUX4 protein is normally made during early development and in the testes.

FSHD is caused by genetic mutations that “turn on” the D4Z4 region, resulting in activation of the DUX4 gene and, consequently, the production of DUX4 protein in cells where this protein normally is not produced. Although the detailed molecular mechanisms remain incompletely understood, abnormally expressed DUX4 protein is believed to be toxic to certain cells, especially muscle cells, which ultimately results in the disease’s symptoms.

Types

FSHD is divided into two types. In both, the end result is abnormal expression of the DUX4 protein, but the underlying genetic changes are different.

Type 1, which accounts for around 95% of cases, is caused by abnormal shortening of the D4Z4 region — patients typically have only 1 to 10 repeats, instead of the usual 11 to 100 or more, which causes the region to get “turned on.”

In type 2, the D4Z4 region gets activated through other mechanisms. Most commonly, type 2 FSHD is caused by mutations in a gene called SMCHD1, which normally is important for “turning off” the D4Z4 region.

Inheritance

Everyone inherits two copies of chromosome 4, one from each biological parent. In about 70%–90% of cases, mutations that cause FSHD are passed from parents to their biological children. In the remaining cases, mutations occur de novo — that is, only in the affected individual.

FSHD is typically inherited in an autosomal dominant pattern, which means that one mutated copy is sufficient to cause the disease. A person with FSHD has a 50% chance of passing the disease-causing mutation to their biological children. In FSHD type 2, patients inherit two independent genetic changes, typically one from each parent.

Symptoms

FSHD is characterized by muscle weakness that mainly affects the face, shoulders, and upper arms. Patients often exhibit “scapular winging,” when the shoulder blades stick out due to weakness in shoulder muscles. Due to facial weakness, patients often cannot purse their lips or turn up the corners of their mouth when smiling, and they often are unable to completely close their eyes while asleep. Muscle wasting in the upper arms can result in the appearance of “Popeye arms,” where the forearms seem abnormally large in proportion to the rest of the arm.

Muscle weakness also can affect the lower legs and hips, and about one in five people with FSHD will eventually rely on a wheelchair for mobility. Some patients with FSHD also experience vision problems or hearing loss associated with the disease. Chronic pain is a common, but often under-recognized symptom of FSHD.

The age at onset and severity varies widely from person to person — some babies with FSHD might show signs of muscle weakness from the moment they are born, while others might go their whole lives without ever noticing symptoms. Symptoms typically start becoming apparent during adolescence, with the majority of FSHD patients displaying noticeable symptoms by the time they are 20.

FSHD is a progressive disease, which means that its symptoms tend to worsen gradually over time. Many patients have described a “stuttering” pattern of disease progression, where symptoms are stable for long periods of time, followed by periods of rapid deterioration.

Management and prognosis

FSHD does not affect lifespan, but it can cause marked disability. There are currently no therapies that can alter the progression of the disease. Management of the disease generally involves working to ease symptoms and providing support to patients to maximize their quality of life.

Many patients benefit from interventions such as physical therapy to help improve motor function. Speech therapy may help those who find talking difficult, and surgeries can alleviate some physical problems such as scapular winging.

 

Last updated: Jan. 20, 2022, by Marisa Wexler MS

 


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