Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy is a genetic disorder that progressively weakens muscles of the face, shoulders, and upper arms, affecting approximately 1 in 8,000 to 20,000 people worldwide and representing the third most common form of muscular dystrophy.

Table of contents

• What is Facioscapulohumeral Muscular Dystrophy?
• Identification Codes and Synonyms
• Affected Anatomy
• Types of FSHD
• Symptoms and Progression
• Genetic Causes
• Diagnosis and Testing
• Management and Treatment Approaches
• Living with FSHD and Outlook

What is Facioscapulohumeral Muscular Dystrophy?

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder in which the muscles of the face, shoulder blades, and upper arms are among the most affected^[1]. The long name comes from Latin and medical terms: facies refers to the face; scapula refers to the shoulder blade; and humerus refers to the upper arm bone that extends from the shoulder to the elbow^[1][2]. The term muscular dystrophy means progressive muscle degeneration, with increasing weakness and atrophy (loss of bulk or shrinkage) of muscles^[1].

FSHD is the third most common type of muscular dystrophy, following Duchenne and Becker muscular dystrophies and myotonic dystrophy^[1][3]. In FSHD, weakness first and most seriously affects the face, shoulders, and upper arms, but the disease usually also causes weakness in other muscles throughout the body^[1].

Identification Codes and Synonyms

FSH, FSHD, Landouzy-Dejerine muscular dystrophy, FSHMD, FSHD

Affected Anatomy

• Face (facial muscles)
• Shoulder blades (scapulae)
• Upper arms (humerus region)
• Lower abdominal muscles
• Lower legs (shin muscles)
• Hips and pelvis
• Core muscles

Types of FSHD

FSHD is classified into two main types based on the genetic mechanism that causes the condition, although both types produce the same symptoms^[2][5].

FSHD Type 1 (FSHD1) accounts for approximately 95% of all cases^[2][5]. This type happens when a gene called DUX4, which is supposed to be inactive in most cells of the body, becomes active. The number of D4Z4 repeats on chromosome 4 is reduced from the normal 11 to 100 repeats down to between 1 and 10 repeats^[3][5]. This contraction of the D4Z4 region leads to the gene becoming reactivated, and the gene then makes proteins that destroy muscle cells^[2].

FSHD Type 2 (FSHD2) accounts for the remaining 5% of cases^[2][5]. Like FSHD1, protein from a reactivated DUX4 gene damages muscle. However, FSHD2 happens when a different gene, most commonly SMCHD1 located on chromosome 18, mutates or changes^[3][5][7]. This mutation affects methylation, creating a situation that turns on the normally inactive DUX4 genes^[2].

Some experts also divide FSHD into adult-onset and infantile-onset forms based on when symptoms appear. The adult-onset form, which includes FSHD that begins in adolescence, is far more common^[1]. Infantile-onset FSHD generally runs a more severe course with regard to muscle weakness, and sometimes also affects hearing and vision^[1][4].

Symptoms and Progression

The estimated prevalence of FSHD is about 4 cases per 100,000 individuals, though some research suggests it could affect as many as 1 in 8,000 people^[1][4]. Symptoms usually begin before age 20 in approximately 90% of FSHD patients, though the onset and severity of the condition varies widely^[1][5]. Milder cases may not become noticeable until later in life, whereas rare severe cases become apparent in infancy or early childhood^[5].

Weakness first and most seriously affects specific muscle groups. In the face, people with FSHD cannot “purse” their lips to whistle or sip through a straw^[2]. They may sleep with their eyes slightly open because they cannot fully close their eyes, which can lead to dry eyes and other eye problems^[2][5]. Facial muscle weakness often makes it difficult to drink from a straw, whistle, or turn up the corners of the mouth when smiling^[5]. For reasons that are unclear, weakness may be more severe on one side of the face than the other^[5].

In the shoulders, FSHD weakens the muscles that hold the shoulder blades in place^[2]. When people with FSHD move their shoulder blades, they stick out and move up toward the neck, making the shoulder blade look like a wing. Healthcare providers call this scapular winging^[2][5]. Weak shoulder muscles cause deformities such as pronounced shoulder blades and sloping shoulders, and weakness makes it difficult to raise the arms above shoulder level^[1][5].

If someone has FSHD, their biceps and triceps are unusually weak, making it hard to lift their arms higher than their shoulders^[2]. Weakness in muscles of the shoulders and upper arms can make it difficult to raise the arms over the head or throw a ball^[5].

Other common symptoms include weak lower abdominal muscles, which make the belly stick out; a sunken breastbone; weak or drooping wrists; chronic fatigue; and pain that can be severe^[2][4]. Chronic pain is present in 50% to 80% of people with this type of muscular dystrophy^[12]. More than 70 percent of people with FSHD experience debilitating pain and fatigue^[4].

FSHD may affect different muscles at different times and usually with asymmetric involvement—meaning one side of the body is affected more than the other^[1][2]. For example, the right arm may be weak but not the left, or both arms may be weak but one will be much weaker than the other^[2].

The muscle weakness associated with facioscapulohumeral muscular dystrophy worsens slowly over decades and may spread to other parts of the body^[5]. Weakness in muscles of the lower legs can lead to a condition called foot drop, which affects walking and increases the risk of falls^[2][5]. Muscular weakness in the hips and pelvis can make it difficult to climb stairs or walk long distances^[5]. About 20 percent of affected individuals eventually require the use of a wheelchair, typically after age 50^[2][4][5].

Weakness of the back muscles can cause scoliosis (curvature of the spine), while weakness of the abdominal muscles can cause lordosis (an exaggerated curvature of the lower back)^[2][5][12].

Additional Complications

Additional signs and symptoms of facioscapulohumeral muscular dystrophy can include mild high-tone hearing loss, particularly high-frequency bilateral hearing loss, and abnormalities involving the light-sensitive tissue at the back of the eye (the retina)^[3][5][7]. These signs are often not noticeable and may be discovered only during medical testing^[5].

Specific eye conditions that may occur include Coats disease, when abnormal blood vessels develop in the retina, and exposure keratitis, which happens when a person cannot close their eye all the way, causing the cornea to become dry^[2].

Rarely, facioscapulohumeral muscular dystrophy affects the heart (cardiac) muscle or muscles needed for breathing^[5][12]. Abnormal heart rhythms may occur, but are rare^[12].

Genetic Causes

FSHD is an inherited autosomal dominant disorder, which means that if either parent carries the gene for the disorder, it may develop in a child^[7][12]. However, in 10% to 30% of cases, the parents do not carry the gene, meaning the condition arose from a spontaneous or new mutation^[12]. About 30 percent of cases arise in families with no prior history^[4].

Both types of FSHD result from changes in a region of DNA near the end of chromosome 4 known as D4Z4^[5]. This region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs long^[5]. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups attached to the DNA. The addition of methyl groups turns off (silences) genes, so hypermethylated regions of DNA tend to have fewer genes that are turned on (active)^[5].

Facioscapulohumeral muscular dystrophy results when the D4Z4 region is hypomethylated, with a shortage of attached methyl groups^[5]. In FSHD1, hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats^[5]. In FSHD2, hypomethylation most often results from mutations in a gene called SMCHD1, which provides instructions for making a protein that normally hypermethylates the D4Z4 region^[5].

The pathology of FSHD is a result of an intricate interaction involving the protein product of the DUX4 gene and the chromosomal location and number of repeats of the D4Z4 macrosatellite^[3]. The DUX4 gene is part of the larger D4Z4 macrosatellite located on chromosomes 4 and 10^[3]. The result of this interaction is the inappropriate expression of the DUX4 protein product^[3].

The DUX4 protein that is normally only expressed in germline tissue becomes expressed in somatic cells, especially myocytes (muscle cells)^[3]. DUX4 protein is especially toxic to myocytes, and this toxicity leads to cell death and muscle atrophy seen in FSHD patients^[3]. The location of the decreased macrosatellite repeats must occur on chromosome 4 to cause pathology; reductions in repeats on chromosome 10 have not been shown to cause disease^[3].

The fewer DUX4 gene copies people with FSHD have, the more severe the disease is likely to be^[19]. People with one to three copies are most likely to get FSHD in childhood. If they have four to seven copies, they might get it in their teens or later. People with eight to 10 copies tend to get it in adulthood^[19].

Diagnosis and Testing

Diagnosing FSHD typically involves a clinical evaluation, a review of medical history, and genetic testing to confirm the diagnosis^[4]. It is important to seek evaluation from a neurologist or neuromuscular specialist experienced in diagnosing FSHD^[4]. A definitive diagnosis makes appropriate management and access to support resources possible^[4].

A physical exam will show weakness of the face and shoulder muscles as well as scapular winging^[12]. Weakness of the back muscles can cause scoliosis, while weakness of the abdominal muscles can be the cause of a sagging belly^[12].

Tests that may be done to diagnose or evaluate FSHD include^[12]:

• Blood creatine kinase levels
• DNA testing and genetic testing of chromosome 4
• Electrocardiogram (ECG)
• Electromyography (EMG)
• Fluorescein angiography
• Hearing tests
• Muscle biopsy (may confirm the diagnosis)
• Visual exam and eye tests
• Cardiac testing
• X-rays of the spine to determine if there is scoliosis
• Pulmonary function tests

Genetic testing is a valuable tool for confirming an FSHD diagnosis^[4]. Testing identifies the genetic changes associated with FSHD, helping to differentiate it from other conditions with similar symptoms^[4]. Diagnostic and prenatal genetic testing are available for FSHD, and pre-implantation genetic diagnosis is available for couples using in vitro fertilization^[7].

Management and Treatment Approaches

There is currently no cure for FSHD, and presently no treatment that can halt or reverse the effects of FSHD^[2][4][8]. However, there are therapies to ease symptoms and help maintain quality of life^[2], and many treatments are already available to manage symptoms and help people live better lives^[9].

Physical and Occupational Therapy

Physical therapy may help maintain muscle strength^[12]. Activity is encouraged, as inactivity such as bedrest can make the muscle disease worse^[12]. It is important to find a practitioner who has some experience in neuromuscular conditions or degenerative conditions, because with FSHD, recovery of muscle is not a realistic goal^[20]. Instead, the aim of therapy is to maintain condition, improve or maintain balance, and support fitness^[20].

Occupational therapy can help improve activities of daily living^[12]. Speech therapy may also be beneficial for some individuals^[12].

Assistive Devices and Equipment

Physical therapists often recommend devices such as back supports, corsets, girdles, and special bras for people with FSHD to help compensate for weakening muscles in the upper and lower back^[8]. Lower leg braces, known as ankle-foot orthoses (AFOs), can compensate for weakening muscles in the lower leg that cause tripping and falling^[8][12]. These may be recommended by a physician or physical therapist and can be purchased as off-the-shelf or custom-made models^[8].

Surgical Interventions

Surgical procedures to stabilize the shoulder blades (scapulae) by attaching them to the ribs have helped some people with FSHD^[8][12]. In this procedure, the scapulae are fixed to the ribs so that they do not move, which gives the patient some leverage with the arm on the side that has had the operation because the scapulae no longer slide around^[8]. Although this type of surgery may actually decrease the arm’s range of motion because the shoulder blade can no longer rotate normally, the ability of the arm to function may be better because the arm’s leverage point is now stable^[8]. It is important to go to a surgeon who fully understands FSHD and has had experience with this exact type of surgery^[8].

Medication Approaches

Medical treatments for facioscapulohumeral muscular dystrophy are relatively few, and none are specific to the disease^[8]. Anti-inflammatory drugs known as nonsteroidal anti-inflammatories (NSAIDs) are often prescribed to improve comfort and mobility^[8]. Antidepressants or antiepileptics are appropriate for chronic pain^[8][12]. Oral albuterol has been studied to increase muscle mass, though not necessarily strength^[10][12].

Several clinical trials have been conducted to test different medications. Albuterol had statistically significant results in three out of four clinical trials, with improved elbow flexor muscle strength^[10]. Vitamin C, vitamin E, zinc gluconate, and selenomethionine showed significant improvement in the maximal voluntary contraction and endurance limit time of quadriceps muscle^[10]. Diltiazem and MYO-029 demonstrated no improvement in function, strength, or muscle mass^[10].

New research has demonstrated that a combined regimen of growth hormone and testosterone is safe, well-tolerated, and is associated with meaningful improvements in muscle mass, strength, and mobility for men living with FSHD^[11]. By the end of six months of treatment, men had gained an average of about 4.5 pounds of lean muscle and lost around 3 pounds of fat, and many of these gains remained even three months after they stopped the hormone injections^[11].

An experimental drug called del-brax (delpacibart braxlosiran), designed specifically to target the molecular cause of FSHD, successfully reduced levels of the rogue DUX4 protein in preliminary clinical trial results^[15]. After four months, del-brax reduced levels of DUX4 in trial participants by an average of more than 50% and levels of DUX4-related proteins by 25%^[15]. Losmapimod, currently in phase I of the ReDUX4 trial, has also showed promising results^[10].

Monitoring and Support

Counseling services from a psychiatrist, psychologist, or social worker may be beneficial^[12]. BiPAP (a breathing support device) may help with breathing if needed, though oxygen alone should be avoided in patients with high CO2 levels^[12].

Multidisciplinary, personalized care is important for managing FSHD^[9]. A wide range of medical specialists and allied health professionals could be involved in care at different stages, including neurologists, genetic counselors, psychologists, physiotherapists, occupational therapists, exercise physiologists, speech therapists, dieticians, ophthalmologists, cardiologists, pain specialists, and respiratory specialists^[20].

Living with FSHD and Outlook

Disability related to FSHD is often minor, and lifespan is most often not affected^[12]. Most people with FSHD have a normal lifespan^[17]. The disease has an unaffected life expectancy, though it is progressive in nature^[2].

The condition is variable, meaning symptoms vary widely in presentation and severity, affecting individuals differently^[4]. FSHD can develop quickly or slowly^[17]. Children with FSHD tend to have more severe cases and over time may lose the ability to walk^[17].

Preliminary evidence suggests that the infantile-onset form is associated with a larger piece of missing DNA^[1]. Infantile-onset FSHD is a more severe course of FSHD, and hearing loss (high frequency bilateral sensorineural), vision problems (Coats’ Disease and retinal telangiectasias), and seizures have been documented in this form^[7].

FSHD strikes men, women, and children of all races and ethnicities^[4]. Ten percent develop symptoms before age 10^[4]. Men often have more symptoms than women^[12]. FSHD generally presents outward signs in 95% of affected individuals by the second decade of life for men and the third decade of life for women^[7].

Possible complications may include decreased mobility, decreased ability to care for oneself, deformities of the face and shoulders, hearing loss, vision loss (rare), and respiratory insufficiency^[12]. It is important to talk with a healthcare provider before having general anesthesia^[12].

Many people with FSHD have scaled back aspects of their lives due to physical challenges and fatigue, finding they are not as socially active as they used to be^[19]. However, treatments should be personalized, and what might be a problem for one person might not be an issue for another^[9]. By using available treatments to manage symptoms and participating in clinical trials when appropriate, people with FSHD can work toward maintaining the best possible quality of life^[9].