Facioscapulohumeral muscular dystrophy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Facioscapulohumeral muscular dystrophy is a disorder characterized by muscle weakness and wasting (atrophy). This condition gets its name from the muscles that are affected most often: those of the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The signs and symptoms of facioscapulohumeral muscular dystrophy usually appear in adolescence. However, the onset and severity of the condition varies widely. Milder cases may not become noticeable until later in life, whereas rare severe cases become apparent in infancy or early childhood.

Weakness involving the facial muscles or shoulders is usually the first symptom of this condition. Facial muscle weakness often makes it difficult to drink from a straw, whistle, or turn up the corners of the mouth when smiling. Weakness in muscles around the eyes can prevent the eyes from closing fully while a person is asleep, which can lead to dry eyes and other eye problems. For reasons that are unclear, weakness may be more severe in one side of the face than the other. Weak shoulder muscles tend to make the shoulder blades (scapulae) protrude from the back, a common sign known as scapular winging. Weakness in muscles of the shoulders and upper arms can make it difficult to raise the arms over the head or throw a ball.

The muscle weakness associated with facioscapulohumeral muscular dystrophy worsens slowly over decades and may spread to other parts of the body. Weakness in muscles of the lower legs can lead to a condition called foot drop, which affects walking and increases the risk of falls. Muscular weakness in the hips and pelvis can make it difficult to climb stairs or walk long distances. Additionally, affected individuals may have an exaggerated curvature of the lower back (lordosis) due to weak abdominal muscles. About 20 percent of affected individuals eventually require the use of a wheelchair.

Additional signs and symptoms of facioscapulohumeral muscular dystrophy can include mild high-tone hearing loss and abnormalities involving the light-sensitive tissue at the back of the eye (the retina). These signs are often not noticeable and may be discovered only during medical testing. Rarely, facioscapulohumeral muscular dystrophy affects the heart (cardiac) muscle or muscles needed for breathing.

Researchers have described two types of facioscapulohumeral muscular dystrophy: type 1 (FSHD1) and type 2 (FSHD2). The two types have the same signs and symptoms and are distinguished by their genetic cause.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Facioscapulohumeral muscular dystrophy is caused by genetic changes involving the long (q) arm of chromosome 4. Both types of the disease result from changes in a region of DNA near the end of the chromosome known as D4Z4. This region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs (3.3 kb) long. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups (consisting of one carbon atom and three hydrogen atoms) 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). Facioscapulohumeral muscular dystrophy results when the D4Z4 region is hypomethylated, with a shortage of attached methyl groups. 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. 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. However, about 20 percent of people with FSHD2 do not have an identified mutation in the SMCHD1 gene, and the cause of the hypomethylation is unknown.

Hypermethylation of the D4Z4 region normally keeps a gene called DUX4 silenced in most adult cells and tissues. The DUX4 gene is located in the segment of the D4Z4 region closest to the end of chromosome 4. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is active, researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

The DUX4 gene is located next to a regulatory region of DNA on chromosome 4 known as a pLAM sequence, which is necessary for the production of the DUX4 protein. Some copies of chromosome 4 have a functional pLAM sequence, while others do not. Copies of chromosome 4 with a functional pLAM sequence are described as 4qA or "permissive." Those without a functional pLAM sequence are described as 4qB or "non-permissive." Without a functional pLAM sequence, no DUX4 protein is made. Because there are two copies of chromosome 4 in each cell, individuals may have two "permissive" copies of chromosome 4, two "non-permissive" copies, or one of each. Facioscapulohumeral muscular dystrophy can only occur in people who have at least one "permissive" copy of chromosome 4. Whether an affected individual has a contracted D4Z4 region or a SMCHD1 gene mutation, the disease results only if a functional pLAM sequence is also present to allow DUX4 protein to be produced.

Studies suggest that mutations in the SMCHD1 gene, which cause FSHD2, can also increase the severity of the disease in people with FSHD1. Researchers suspect that the combination of a contracted D4Z4 region and a SMCHD1 gene mutation causes the D4Z4 region to have even fewer methyl groups attached, which allows the DUX4 gene to be highly active. In people with both genetic changes, the overactive gene leads to severe muscle weakness and atrophy.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

FSHD1 is inherited in an autosomal dominant pattern, which means one copy of the shortened D4Z4 region on a "permissive" chromosome 4 is sufficient to cause the disorder. In most cases, an affected person inherits the altered chromosome from one affected parent. Other people with FSHD1 have no history of the disorder in their family. These cases are described as sporadic and are caused by a new (de novo) D4Z4 contraction on one copy of a "permissive" chromosome 4.

FSHD2 is inherited in a digenic pattern, which means that two independent genetic changes are necessary to cause the disorder. To have FSHD2, an individual must inherit a mutation in the SMCHD1 gene (which is located on chromosome 18) and, separately, they must inherit one copy of a "permissive" chromosome 4. Affected individuals typically inherit the SMCHD1 gene mutation from one parent and the "permissive" chromosome 4 from the other parent. (Because neither parent has both genetic changes in most cases, they are typically unaffected.)

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Facioscapulohumeral muscular dystrophy has an estimated prevalence of 1 in 20,000 people. About 95 percent of all cases are FSHD1; the remaining 5 percent are FSHD2.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Elevated circulating creatine kinase concentration · Very frequent (99-80%)

The activity of creatine kinase in the blood circulation is above the upper limit of normal.

Hyperlordosis · Very frequent (99-80%)

Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.

Mask-like facies · Very frequent (99-80%)

A lack of facial expression often with staring eyes and a slightly open mouth.

Scapular winging · Very frequent (99-80%)

Abnormal protrusion of the scapula away from the surface of the back.

Skeletal muscle atrophy · Very frequent (99-80%)

The presence of skeletal muscular atrophy (which is also known as amyotrophy).

Progressive muscle weakness · Very frequent (99-80%)

Abdominal wall muscle weakness · Frequent (79-30%)

Decreased strength of the abdominal musculature.

Abnormal retinal vascular morphology · Frequent (79-30%)

A structural abnormality of retinal vasculature.

Other findings in the same source

From: Orphanet

Additional reported features include Beevor's sign (Frequent (79-30%)); Camptocormia (Frequent (79-30%)); Chronic pain (Frequent (79-30%)); Conjunctivitis (Frequent (79-30%)); Decreased facial expression (Frequent (79-30%)); Distal upper limb muscle weakness (Frequent (79-30%)); EMG: myopathic abnormalities (Frequent (79-30%)); Foot dorsiflexor weakness (Frequent (79-30%)); Gait disturbance (Frequent (79-30%)); Keratitis (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Facioscapulohumeral muscular dystrophy is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Facioscapulohumeral muscular dystrophy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.