Symptom onset typically occurs during the second decade of life. Rare, severe cases may be associated with muscle dystrophy in childhood ; some patients may not present any symptoms until adulthood .
For unknown reasons, muscle weakness and atrophy is generally asymmetric.
Initially, muscle weakness affects facial muscles orbicularis oris, orbicularis oculi and zygomaticus. Consequently, movements requiring contraction of these muscles are restricted. The orbicularis oris muscle encircles the mouth and is needed to bring one's lips forward in order to whistle, drink from a straw, pronounce certain labial sounds or to adopt a mimic expression of surprise. Lid closure is mediated by the orbicularis oculi muscle. FSHD patients are frequently unable to completely close their eyelids, a condition that brings forward the additional issue of insufficient distribution of lacrimal fluid over the cornea. This may lead to dry eyes and ultimately to keratoconjunctivitis sicca. Finally, contraction of the zygomaticus muscle results in an upward movement of the mouth's angles while smiling. This expression may be lost in individuals suffering from FSHD.
Most patients develop shoulder weakness within a short period of time after symptom onset. The deltoid muscle is usually not affected. Scapula alata, i.e., wing-like protrusion of the patient's shoulder blades, is the most characteristic symptom of scapular involvement. The spine of the scapula is generally well visible. Shoulder weakness limits the patient's ability to lift any object above their head, even their own arms. External upper arm rotation and - with onset of humeral muscle dystrophy - additional arm movements are impaired.
Abdominal muscles, pelvic muscles and musculature of the lower leg may be affect during later stages of the disease. Because abdominal muscles play a major role in maintenance of a healthy posture, weakness of those muscles may lead to lordosis. Of note, lower abdominal muscles are generally more severely affected than upper abdominal muscles, which results in the Beevor sign. With regards to muscles of the pelvic region, adduction and abduction of the lower limbs may be restricted as well as extension of the hip joint. Loss of contractility of lower leg muscles may interfere with ankle flexion and cause foot drop, a condition associated with a characteristic alteration of gait and an increased risk of falls.
In rare cases, mild hearing loss and vascular retinopathy may be present . Patients don't usually claim hearing or visual impairment to interfere with their everyday life. Severe cases of FSHD have also been related with epilepsy and mental retardation .
The medical history of a patient's family generally implies FSHD upon detection of first symptoms. If a genetic screen has previously been conducted due to familial accumulation of the disease, the patient may even report genetic predisposition to muscle dystrophy. Tentative diagnosis of FSHD is confirmed by means of clinical examination.
Additional diagnostic measures may be indicated in case of doubt. The most reliable test is a genetic screen for FSDH1- or FSDH2-associated gene defects. Laboratory analyses of blood samples should reveal elevated levels of creatine kinase. Additionally carbonic anhydrase and troponin I have been proposed as biomarkers of FSHD . Electromyography may be carried out and should prove reduced electrical activity of affected muscles. Muscle biopsies are not indicated unless the aforementioned tests provide results not consistent with FSHD.
To date, there is no causative therapy for FSHD.
A variety of drugs has been tested for their efficacy in FSHD and recently, histone methylation has been proposed as a new target of therapy. Promising results have not yet been published. Although sympathomimetics may slightly increase lean body mass, muscle and grip strength, benefits don't outweigh possible side effects. Initially, similar effects have been reported for supplementation of creatine monohydrate, but results could not be confirmed in later studies.
Most patients with shoulder weakness and winged scapulae preserve function of the deltoid muscle. If that's the case, shoulder blades may be fixed against the thoracic wall by means of scapulothoracic arthrodesis in order to improve upper limb function .
Patients suffering from walking difficulties due to foot drop may benefit from an ankle-foot orthosis. It should be well adapted to the patient's anatomy. In severe cases, i.e., if control of knee movements is also reduced, orthoses should involve the knee joints.
Patients should be encouraged to realize low-intensity aerobic exercises .
Since the degree of repeat contraction on chromosome 4 has been related to the severity of FSDH1, genetic analysis may allow for an estimation of the outcome in a particular case of this type of muscle dystrophy. Shorter fragments and less repeats increase the likelihood of severe FSHD.
Muscle weakness and atrophy typically spreads from face to shoulders and upper arms. Little can be done to stop that progress. According to current knowledge, it is not possible to predict involvement of pelvic and lower leg musculature. Cardiac and respiratory muscle function are generally not compromised by FSHD. Thus, many patients may require a wheelchair at some point in their lives, but overall life expectancy is not reduced.
About 95% of all FSHD patients present a decreased number of certain sequence repeats on the long arm of chromosome 4 (position 4q35) , but a gene mutation causing that phenomenon has not yet been identified. Molecular biological analysis of DNA samples obtained from more than 150 FSHD patients revealed an inverse correlation between the number of macrosatellite D4Z4 repeats and the likelihood of severe FSHD . While up to 100 D4Z4 repeats - each measuring about 3 kb in length - are considered physiological, FSHD patients present only 10 or even less. In detail, restriction digest yielded an Eco RI fragment larger than 30 kb in most healthy individuals, while more than 50% of test subjects with a fragment measuring less than 20 kb developed severe muscle dystrophy. Eco RI fragments shorter than 15 kb were associated with severe FSHD in all cases. Interestingly, complete absence of D4Z4 does not result in FSHD.
The majority of the remaining 5% of FSHD cases can be ascribed to mutations of gene SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which is ubicated on the short arm of chromosome 18 (position 18p11).
Of note, few FSHD patients don't present either of the aforementioned genetic defects. To date, these cases are deemed sporadic. Possibly, they are related to as of yet undefined gene variants. Also, epigenetic mechanisms have repeatedly been proposed to contribute to severity of FSHD. Their precise pathogenetic role is still unclear and it is not known whether epigenetic modifications may cause a possible third type of the disease without an underlying sequence alteration being present.
FSHD is the third most common heritable muscle dystrophy. Its prevalence has been estimated to be about 5 per 100,000 individuals, a rate only surpassed by myotonic muscular dystrophy and Duchenne muscular dystrophy .
No racial predilections have been described.
It has been reported that males are more frequently affected than females. Inheritance doesn't account for this observation, which consequently requires further verification, but may give important hints as to underlying pathogenetic mechanisms.
Most patients diagnosed with FSHD are adolescents.
In FSHD1, reduced numbers of macrosatellite D4Z4 repeats in chromosome 4 cause hypomethylation and chromatin relaxation of that same chromosome. This is associated with loss of heterochromatic features, i.e., binding to histones and other proteins that render DNA rather inactive. Repeat contractions are therefore linked to increased expression of certain genes, namely of DUX4 (double homeobox 4). The DUX4 gene encodes for a sequence-specific transcription factor. DUX4 expression is generally considered "toxic" since it may interfere with myogenesis, trigger myocyte apoptosis and cause myositis . Other genes whose expression may be elevated in FSHD1 patients are ANT1 (adenine nucleotide translocase type 1), FRG1 and FRG2 (FSHD region gene 1 and 2).
It has been proposed that diminished numbers of D4Z4 repeats in chromosome 4 are not sufficient to induce FSHD1. Instead, single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat seem to cause stabilization of DUX4 transcripts . According to current knowledge, both repeat contractions and single-nucleotide polymorphisms are required for induction of muscle dystrophy.
Mutation of SMCHD1, located on chromosome 18 and responsible for FSHD2, also causes hypomethylation and chromatin relaxation of chromosome 4. Thus, it triggers the same pathogenetic mechanisms as described for D4Z4 repeat contraction. This explains why two genetic defects provoke identical symptoms of muscle dystrophy.
No specific measures can be recommended to prevent FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is a rather common genetic disorder associated with metabolic and structural alterations of facial, shoulder and upper arm musculature that lead to progressive weakening and atrophy of the corresponding muscles .
Most cases can be ascribed to determined gene defects, while a minority of FSHD cases is deemed sporadic. Presumably, the latter also result from genetic disorders that have, however, not yet been characterized in detail. According to the gene variant causing FSHD in a determined patient, two types of the disease may be distinguished: FSHD1 is triggered by alterations on chromosome 4, FSHD2 results from gene variants located on chromosome 18. They don't differ in clinical presentation.
Symptom onset usually occurs during the second decade of life, but severe cases may already be diagnosed in childhood and sometimes, muscle weakness is not observed before adulthood. The disease typically spreads in an asymmetric manner, from facial muscles to shoulders and upper arms and within several years or decades. Affected individuals may initially report difficulties to perform tasks like whistling, drinking from a straw, smiling, grimacing or pronunciation of determined sounds. Eyelid movements may be affected and if lid closure is incomplete, patients may present with dry eyes or keratoconjunctivitis sicca. As soon as muscle dystrophy reaches the shoulder's musculature, arm power starts to diminish. It may become impossible for an FSHD patient to raise their arms or other weights above their head. External rotation of the upper arm is restricted. Over time, muscle atrophy may lead to winged scapulae and a pronounced scapular spine. Involvement of upper arm muscles further limits the patient's ability to perform day-to-day activities that depend on minimal arm power. In some cases, muscle dystrophy spreads even further and affects the pelvic region or lower legs, which causes difficulties while walking, running or climbing stairs. Some FSHD patients may need to use a wheelchair. To date, the reasons for FSHD-associated selective impairment of muscle function are not known.
Causative treatment for FSHD is not available. Supportive therapy mainly consists in orthopedic measures that compensate for the loss of muscle function.
FSHD is a genetic disorder inherited with an autosomal dominant trait, i.e., if one parent inherits a mutated gene to their child, the presumably healthy gene inherited from the other parent is not able to compensate the defect. Men and women may both be affected by this disease.
Two genes have been identified as possible causes of FSHD. Both alter gene expression and muscle cell metabolism, which ultimately leads to muscle cell death, muscle weakness and atrophy.
Symptom onset usually occurs during the second decade of life, rarely in infancy or adulthood. Facial muscles are affect first. Subsequently, shoulder and upper arm muscles are compromised. In some patients, the disease may even lead to functional impairment of musculature of the pelvic region and lower legs.
The following symptoms may be observed:
Genetic screens and identification of the underlying gene defect confirm FSHD diagnosis. However, a familial history of FSHD and observation of characteristic symptoms does already prompt a strong suspicion.
There is no causative treatment for FSHD. While orthopedic measures may compensate for muscle weakness in certain regions of the body, i.e., the inability to lift the tip of the foot may be countervailed with an ankle-foot orthosis, about one out of four FSHD patients will require a wheelchair within less than a decade.
Life expectancy is unaltered.