FSHD is a common form of muscular dystrophy defined by a specific set of symptoms. Its major symptom is the progressive weakening and loss of skeletal muscles. The usual location of these weaknesses at onset is the origin of the name: face (facio), shoulder girdle (scapulo) and upper arms (humeral). Early weaknesses of the muscles of the eye (open and close) and mouth (smile, pucker, whistle) are distinctive for FSHD. These symptoms, in combination with weaknesses in the muscles that stabilize the scapulae (shoulder blades), are often the basis of the physician’s diagnosis of FSHD.

Although the progression of FSHD is quite variable, it is usually relatively slow. Other skeletal muscles invariably weaken. Involvement of muscles of the foot, hip girdle and abdomen is common. With FSHD, most affected people develop unbalanced (side-to-side) weaknesses. The reason for this asymmetry is unknown.

In most cases, FSHD muscle involvement starts in the face and slowly progresses to the shoulder and upper-arm muscles and then down to the abdominal and foot-extensor muscles. Foot drop and foot weakness are early manifestations.

Initial signs of FSHD include difficulty reaching above the shoulder level, foot drop, scapular winging and facial weakness. Weakness in the abdominal muscles can cause a protuberant abdomen and lumbar lordosis. The lower abdominal muscles are usually weaker than the upper abdominal muscles. This distribution of weakness causes a positive Beevor’s sign that is not seen in many other diseases and is a physical characteristic very specific to FSHD.

In more than half of FSHD cases, there are other symptoms including high-frequency hearing loss and/or abnormalities of blood vessels in the back of the eye. The vascular abnormalities in the back of the eye lead to visual problems in only about 1% of the cases. Since these abnormalities are not exclusive to FSHD, one must bear in mind that their presence alone, in an FSHD at-risk individual, is insufficient for a diagnosis of FSHD.

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Facioscapulohumeral muscular dystrophy type 1A (FSHD1A or FSHMD1A) is the more common form of FSHD. A conservative estimate of incidence is 1 in 14,000 births throughout the world; however, due to increased experience with FSHD, population-based research and improved genetic testing, this estimate may be low; actual incidence may be 1 in 7,500. In FSHD1A the disease is associated by genetic testing with the deletion of 3.3-kb repeats from a chromosomal tandem repeat called D4Z4 located near the end of chromosome 4 at the 4q35-qter location.

The D4Z4 region is a polymorphic variable number tandem repeat (VNTR) array consisting of 3.3 kb units. Unaffected individuals have a chromosome 4 D4Z4 array that has a span of 11 to 150 contiguous units. In individuals with FSHD, the chromosome 4 D4Z4 repeat array is contracted to a range between 1 to 10 contiguous units. Over time and through evolution the D4Z4 repeat array propagated to other parts of the human genome. D4Z4 is also present on the sub-telomere of chromosome 10. However, a shortened D4Z4 repeat on 10q26 does not cause FSHD.

Additionally, it is currently thought that a short array caused by the deletion of the D4Z4 region on chromosome 4q35 alone does not cause FSHD. Going towards the end of the chromosome beyond (distal to) the D4Z4 region, a specific genetic sequence has been identified as being needed to cause FSHD. Genetic variations of this type are called allelic subtypes or specificities; this particular variation is called allele type 4qA and 4qB. The two alleles are equally distributed in the entire population. Interestingly, patients with FSHD carry the 4qA variant in parallel to the shortened D4Z4 repeat region. Individuals who have a shortened D4Z4 array and a 4qB allele are unaffected for FSHD. The defining genetic feature that distinguishes the two allelic variants is the presence of a 6.2 kilobase β-satellite repeat on the 4qA allele.

The online database Online Mendelian Inheritance in Man (OMIM) is an excellent source for further information on the science and medicine of FSHD 1A. OMIM was designed for use by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. OMIM is developed and maintained by the National Center for Biotechnology Information (NCBI). This database is a catalog of human genes and genetic disorders and has hyperlinks to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere.

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Facioscapulohumeral muscular dystrophy type 1B (FSHD1B or FSHMD1B) is a much rarer type, occurring in several dozen well documented families. The incidence of FSHD1B is not known at this time, but is unlikely to exceed 2% of all cases of FSHD. In FSHD1B the disease is NOT associated with the deletion of 3.3-kb repeats from a chromosomal tandem repeat called D4Z4 located near the end of chromosome 4 at the 4q35-qter location. FSHD1B may be caused by different genes, located on the same or different chromosomes. 

FSHD1B may also be caused by proximal and distal deletions that extend into D4Z4 that cause the standard genetic test to be “negative” even though the patient has the requisite number of deletions to cause FSHD. FSHD1B is also referred to as non-chromosome 4 linked FSHD. A common misconception is that FSHD1B is linked to the D4Z4 that is also present on the sub-telomere of chromosome 10. In fact, however, a shortened D4Z4 repeat on 10q26 does not cause FSHD or have anything to do with FSHD1B.

The online database Online Mendelian Inheritance in Man (OMIM) is an excellent source for further information on the science and medicine of FSHD 1B. OMIM was designed for use by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. OMIM is developed and maintained by the National Center for Biotechnology Information (NCBI). This database is a catalog of human genes and genetic disorders and has hyperlinks to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere.

This information was graciously provided by the FSH Society

By going from the large (muscle cells) to the small (DNA), one can partially understand the cause and origin of FSHD. DNA, short for deoxyribonucleic acid, is a long molecule found in the cells of our body. In association with some proteins, DNA makes up our chromosomes. It holds the genetic instructions for our hereditary traits. Discrete segments of DNA, called genes, determine specific traits. Taken together, the combination of approximately 24,000 genes makes each of us “an original.”

A sudden structural change in DNA — a mutation — causes FSHD. The FSHD gene(s) is still unknown, but its approximate location is toward the end of the DNA of the long arm of chromosome 4. The specific genetic location of the FSHD deletion is 4q35 in the D4Z4 DNA region.

Researchers are investigating the molecular connection between this deletion and FSHD. The size of the deletion has a relationship to the severity of the disease — patients with the fewest repeats (the largest deletion) typically have the most severe symptoms.. It is not yet certain whether the deleted DNA contains an active gene or changes the regulation or activity of a nearby FSHD gene (a position effect). DNA, RNA, and protein research is ongoing in this area.

Perhaps 2% of FSHD cases are not linked to the 4q35 deletion on chromosome 4. Their linkage to any other chromosome or genetic feature is under investigation.

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Most individuals with FSHD inherit the mutation from a parent with the disease. DNA is the means of transmission of inheritable traits from parent to child.

Chromosomes are the vehicles for these DNA transfers from one generation to the next. Each chromosome contains a long, thread-like strand of DNA. Human cells usually contain 46 chromosomes, 23 from each parent. Children inherit one member of each of the 23 pairs of chromosomes from each parent. Forty-four of the chromosomes, also called autosomes, are homologous pairs (numbered 1 through 22), with each strand of the pair having the same size, order and arrangement with genes for the same traits in the same position on the chromosome. The remaining chromosome pair consists of the nonhomologous sex chromosomes X and Y. A mother donates an X chromosome, and a father donates either an X or Y chromosome. Therefore, males have one X chromosome and one Y chromosome, while females have two X chromosomes.

FSHD is the result of a DNA mutation on one member of the chromosome 4 pair. FSHD is highly penetrant. This means that when a person inherits a chromosome 4 with the FSHD mutation, there is a high probability that discernible muscle weaknesses will develop. Since weakness still occurs in the presence of the normal member of the chromosome 4 pair, the disease is considered dominant. FSHD is, therefore, a dominant inherited disease, meaning only one parent has to have the disease gene or deletion for his or her child to inherit FSHD. Since each parent donates only one member of each chromosome pair to a child, the probability of passing the disease to an offspring is 50%. However, 50% probability means that in a population of 1,000 people this will happen about 50% of the time. In an individual family this can happen 100%, 0%, or anything in between.

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Sporadic FSHD cases are those resulting from a new mutation. Studies report from 10% to as high as 33% of FSHD cases as sporadic (de novo mutation). Approximately 20% of reported sporadic cases are those inherited from a seemingly unaffected parent who is a “germline mosaic,” meaning that only the mother’s or father’s germ cells (the egg or sperm) is affected. When a germline mosaic is involved, the parent appears unaffected but the children are at risk.

In the remaining 80% of sporadic cases, neither parent’s genes are affected; a new spontaneous mutation results in a chromosome 4 deletion that causes FSHD. When the 4q35 deletion fragment appears in a sporadic FSHD case, it is transmitted in an autosomal dominant (only one parent needs to be affected) manner to succeeding generations. The probability, then, of passing the disease to an offspring is 50%.

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It is difficult to calculate the exact incidence of FSHD. The most common form of FSHD is FSHD type 1A (chromosome 4-linked FSHD). A conservative estimate of incidence is 1 in 14,000 births throughout the world; however, due to increased experience with FSHD, population-based research and improved genetic testing, this estimate may be low; actual incidence may be 1 in 7,500.

FSHD type 1B (non-chromosome 4-linked FSHD) is much rarer than FSHD type 1A (chromosome 4-linked FSHD). There is no generally accepted estimate of its incidence, but incidence is unlikely to exceed 2% of all cases of FSHD.

Infantile FSHD (IFSHD) is characterized by onset in early childhood. There is no generally accepted estimate of its incidence, but it is rare.

FSHD occurs in all racial groups and with equal frequency in both sexes.

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Although the FSHD gene is present at birth, weaknesses are generally not noticeable until the second decade. Sometimes muscle weaknesses are slight throughout adulthood. A physician can usually recognize and diagnose FSHD beyond the age of 20. However, it is important to realize that the onset of FSHD is variable.

In infantile FSHD (IFSHD), a young child or an infant develops symptoms. In IFSHD there are facial weaknesses during the first two years of life in addition to other typical muscle weaknesses of FSHD. Some of these children also experience early hearing losses and retinal abnormalities.

Early onset and infantile cases of FSHD often pose special challenges arising from severity of the symptoms and schooling issues.

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Predicting the course and outcome of the disease, i.e., the prognosis, has its clinical certainties and uncertainties. There is certainty that some skeletal muscles will weaken and waste throughout life and that this can, and often does, cause limitations on personal and occupational activities. FSHD appears not to diminish the intellect. The heart and internal (smooth) muscles seem spared and, with rare exceptions, those with FSHD have a normal life span.

There are uncertainties. The rapidity and extent of muscle loss differ considerably among FSHD patients — even among members of the same family. Some report few difficulties throughout life, while others need a wheelchair as walking becomes too difficult or impossible. The degree of severity in an FSHD parent cannot accurately predict the extent of disability that may develop in that parent’s child.

Muscle and motion are an important part of the full expression of much of life. Often, there are losses difficult to define in clinical terms. Interactions with family, friends and associates may become limited. The accompanying losses often eclipse the clinical certainties and are an unspoken and significant part of the FSHD prognosis.

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Yes. If one has a blood parent, sibling or other relative who has the FSHD mutation, there may be a risk of carrying that mutation. Often, when a person is diagnosed, the disease is discovered to be throughout the extended family tree and over many generations. It is important to be aware that there may be other family members who are affected but unaware that they may have FSHD or may be at risk for FSHD. Professionals with knowledge of genetics and inheritance of FSHD can advise them regarding that risk.

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Yes. Even adults at risk, with no obvious symptoms, should avail themselves of a clinical diagnosis if they wish reassurance. Examinations by clinicians familiar with the disease are quite dependable when there are symptoms that follow an expected location and pattern of weakening muscles. By the age of 20, muscle weakness can be found approximately 95% of the time in affected individuals.

Often the physician will supplement a physical examination with inquiries about a possible family history of FSHD, measurement of specific enzyme levels in the blood, an electromyograph (EMG), and/or a muscle biopsy. An EMG records abnormal electrical activity of a functioning skeletal muscle. A biopsy consists of a small piece of muscle tissue analyzed for visible abnormalities.

A thorough examination will detect the disease in approximately 95% of affected individuals age 20 or older. However, the diagnosis may still be equivocal at younger ages and with some at-risk adults with mild or asymptomatic cases. This uncertainty can occur during years when there are important vocational, marital and family planning choices at issue. This has created a real need in the FSHD at-risk population for a DNA test for the disease.

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Yes. There is a DNA test for FSHD. It is highly reliable for most cases. The test detects the 4q35 DNA deletion described earlier. Although several factors may occasionally complicate the test, confirmation of the 4q35 deletion is 98% reliable as a presumptive diagnosis of FSHD. The test requires no more than a small amount of blood that one’s physician sends to a testing laboratory. The laboratory extracts sufficient DNA for the test from the cells present in the blood. An individual should consult their own physician and the laboratories about the DNA diagnostic test.

Currently, there is no DNA test available for those cases where there is no linkage between FSHD and chromosome 4.

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Yes. Using the same technology as the DNA test described above, prenatal testing is possible. An individual who is interested in a prenatal test for FSHD should consult with his or her physician.

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There is no treatment or cure yet for FSHD. There are, however, things that can be done to alleviate its effects, including meeting with knowledgeable health practitioners.

Neurologists are often the primary physicians in muscle disease clinics since muscles do their work through stimulation by nerves. Physiatrists are physicians who work with chronic neuromuscular conditions. Periodic visits with a neurologist or physiatrist are useful to monitor the progress of FSHD and to obtain referrals to other professionals and services. An orthopedist (a physician concerned with the skeletal system and associated muscles, joints and ligaments) can offer advice about mobility issues and other functional problems of the muscular/skeletal system.

Physical therapy, including light exercise, helps preserve flexibility. Swimming is especially helpful in this regard by making many movements easier. One should stay as active as possible, with rest breaks as needed during exercise and activities.

Occupational therapy can help with suggestions for adaptations and physical aids that can often partially free an FSHD patient from some constrictions of the disease. Foot drop can sometimes be managed with ankle-foot orthotics (AFOs) and knee-ankle-foot orthotics (KAFOs).

Dietitians can help maintain a good diet and avoid unnecessary weight to reduce stress on already weakened muscles. In addition, speech and hearing therapists can help with limitations imposed by hearing loss and weakened facial musculature to improve speech and communication.

Sometimes a surgeon attaches the scapulae (shoulder blades) to the back to improve motion of the arms. An individual who is considering such surgery should consult with their neurologist or physiatrist and an orthopedic surgeon. Discussion of this procedure with individuals who have undergone the surgery is important.

Pain is part of FSHD in many patients. No specific treatments are available. Pain medication and mild physiotherapy are often prescribed with moderate results.

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Yes. Respiratory involvement can be seen. Evaluation of the symptoms and signs of respiratory insufficiency should be sought during routine clinic visits in patients with moderate to severe FSHD. Regular monitoring of respiratory function is suggested as one might experience insufficiency over a long period of time without presenting signs.

Symptomatic respiratory insufficiency can be initially managed with nighttime non-invasive pressure support e.g. a BiPAP machine. In very severe cases, patients may require the use of a ventilator. For FSHD patients with respiratory insufficiency, in standard practice, trauma (ER, ICU), surgery and anesthesiology settings, care should be taken not to suppress respiratory drive with narcotics unless it is a situation of palliative care. It is important to notify the doctors about FSHD and any respiratory problems the patient might have or be at risk for.

Oxygen supplementation can be detrimental to patients with hypercarbic (high CO2) respiratory failure and lead to worsening CO2 levels. Oxygen should generally not be administered unless BiPAP or similar ventilatory support is also being used. Your physician and a pulmonologist can help you periodically monitor CO2 levels in the office or pulmonary function lab in the hospital.

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The following frequently asked questions are found at Understanding Clinical Trials at ClinicalTrials.gov site and provide detailed information about clinical trials. This information may be helpful when deciding whether to join a trial.

http://www.clinicaltrials.gov/ct2/info/understand

What is a clinical trial? Why participate in a clinical trial?
Who can participate in a clinical trial?
What happens during a clinical trial?
What is informed consent?
What are the benefits and risks of participating in a clinical trial?
What are side effects and adverse reactions?
How is the safety of the participant protected?
What should people consider before participating in a trial?
What kind of preparation should a potential participant make for the meeting with the research coordinator or doctor?
Does a participant continue to work with a primary health care provider while in a trial?
Can a participant leave a clinical trial after it has begun?
Where do the ideas for trials come from?
Who sponsors clinical trials?
What is a protocol?
What is a placebo?
What is a control or control group?
What are the different types of clinical trials?
What are the phases of clinical trials?
What is an “expanded access” protocol?

This information was graciously provided by the FSH Society