NORD gratefully acknowledges Clara Hageman, Editorial Intern from the University of Notre Dame, and Kathryn R. Wagner, MD, PhD, Director, Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Professor of Neurology and Neuroscience, Johns Hopkins School of Medicine, for assistance in the preparation of this report.
Facioscapulohumeral muscular dystrophy (FSHD) is a disorder characterized by muscle weakness and wasting (atrophy). The disorder gets its name from muscles that are affected in the face (facio), around the shoulder blades (scapulo), and in the upper arms (humeral). Hamstring and trunk muscles are affected even more but are less well recognized. Symptoms usually appear before age 20, but can begin in infancy or later in adulthood. Severity of the condition varies widely and some people remain asymptomatic. FSHD is most typically characterized by relatively slow disease progression. Specific symptoms and findings may also vary in range and severity, including among affected members of the same family. Life expectancy is not shortened. FSHD is usually inherited as an autosomal dominant genetic condition.
FSHD may initially involve weakness of muscles of the face, shoulder girdle and arms. Facial weakness may result in limited movements of the lips, causing difficulties whistling, using a straw, or puckering the lips. Affected individuals may also develop a distinctive “mask-like” facial appearance. Upper facial weakness may also lead to an inability to completely close the eyes during sleep.
FSHD is also typically associated with weakening and atrophy of muscles of the neck and shoulder blades and muscles at the front and back of the upper arms (biceps and triceps brachii muscles). With disease progression, there is a decrease in the ability to flex and rotate the shoulder outward; instability of muscles of the shoulder blades; and “scapular winging,” the most common initial finding, characterized by abnormal prominence of the borders of the shoulder blades. This finding tends to become more obvious when affected individuals attempt to raise their arms to the side (laterally). They often are unable to elevate their arms above the head or, in some people, to shoulder level due to muscle weakness and an inability to fixate the shoulder blades. In addition, when viewed from the front, the collarbones (clavicles) may appear to sag. Some affected individuals may also develop wrist drop or downward flexion of the wrist due to weakness of certain muscles of the fingers and hands.
FSHD may also be characterized by weakness and atrophy of other muscles, including abdominal wall, hip, and thigh muscles. Involvement of the muscle that rotates and moves the thigh outward (gluteus medius) may cause affected individuals to sway or lurch toward the affected side while walking (Trendelenburg gait). There may also be weakness of muscles of the lower legs and feet. Such involvement may lead to a condition known as footdrop, which is characterized by an impaired ability to flex or bend the foot upward. In some affected individuals, involvement of certain muscles may result in unusually pronounced inward curvature of the lower region of the spine (lordosis) or abnormal front-to-back and sideways spinal curvature (kyphoscoliosis).
For unknown reasons, in most individuals with FSHD, the degree of muscle weakness may differ from one side of the body to the other (asymmetrical).
Those with the disorder may have relatively slow or moderate progression of muscle weakness or, in some cases, apparently non-progressive involvement of certain muscles. However, evidence suggests that the disease course is most frequently characterized by slow progression with short periods of rapid muscle deterioration. Associated muscle weakness may result in minimal disability or, in other people, lead to difficulties speaking; abnormalities in the manner of walking (gait disturbances); and/or an impaired ability to perform certain activities of daily living. In approximately 20% of those affected, disease progression may lead to severe muscle weakness that necessitates the use of a wheelchair or other mobility equipment. Families have been described in which disease manifestations ranged from minor facial weakness in a parent to severe infantile onset in an affected child.
In some individuals with FSHD, particularly those with early onset, the disorder may also be associated with hearing impairment and/or abnormalities of blood vessels within the nerve-rich, innermost membrane of the eye (retinal vasculopathy) that may, in rare cases, lead to visual impairment.
Two types of FSHD have been described, FSHD1 (95% of those affected) and FSHD2 (5% of those affected). FSHD1 and FSHD2 have the same signs and symptoms but different genetic causes.
FSHD1 is caused by abnormal expression of the DUX4 gene, which is located in the D4Z4 region of chromosome 4. Normally, the DNA in the D4Z4 region is hypermethylated (has many methyl groups: 1 carbon atom and 3 hydrogen atoms) and includes 11-100 repeated segments of DNA. In individuals with FSHD1, this region of chromosome 4 is shortened and contains 1-10 repeats and fewer methyl groups. The lack of methyl groups allows the DUX4 gene to be “turned on” and produce DUX4 protein in cells and tissues where it is usually not produced, resulting in progressive muscle weakness and atrophy. Generally, a smaller number of repeats is associated with more severe disease.
FSHD1 is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
In approximately 30 percent of individuals with FSHD1, there is no apparent family history of the disorder and in these people FSHD is thought to be caused by new mutations.
FSHD2 is also an autosomal dominant genetic condition. People with FSHD2 have a mutation in the SMCHD1 gene that shortens the DNA of the D4Z4 region resulting in fewer methyl groups, allowing misexpression of the DUX4 gene and resulting in progressive muscle weakness and atrophy.
FSHD appears to affect males and females in relatively equal numbers. The estimated prevalence is between four and ten per 100,000 people.
FSHD may be diagnosed based upon a thorough clinical examination, identification of characteristic physical findings, a complete individual and family history, and various specialized tests. In some affected individuals, laboratory studies may reveal elevated levels of a particular enzyme in the fluid portion of the blood (serum creatine kinase). Tests may also be conducted to record electrical activity in voluntary (skeletal) muscles at rest and during muscle contraction (electromyography [EMG]). Surgical removal (biopsy) and microscopic examination of small samples of muscle tissue is generally not informative in FSHD.
Family members of those diagnosed with FSHD should also receive thorough clinical examinations to help detect any symptoms and signs that may be associated with FSHD.
Molecular genetic testing to determine the number of repeats in the D4Z4 region of chromosome 4 is available to confirm the diagnosis of FSHD1. Most affected individuals have fewer than 10 repeats. Molecular genetic testing for mutations in the SMCHD1 gene associated with FSHD2 is available and may be indicated if the D4Z4 region is not contracted (shortened).
The treatment of FSHD is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the treatment of neurological disorders (neurologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.
Disease management may include orthopedic measures and physical therapy to help maintain muscle flexibility and manage pain. Various physical and adaptive aids may be helpful in performing certain activities. Ankle-foot orthotics can help with walking. In some cases, severe muscle weakness may necessitate the use of wheelchairs, motorized carts, and other mobility and physical aids.
In addition, speech therapy, use of appropriate assistive devices, and/or other supportive techniques may help to improve speech and communication problems associated with hearing impairment and/or facial weakness.
In some people, recommended treatment may include surgery to mechanically attach the shoulder blades to the chest wall in order to help stabilize the scapulae and improve mobility of the upper arms.
Testing for retinal eye problems may be indicated for those with severe disease. Hearing testing may be indicated for children and some adults.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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