Facioscapulohumeral muscular dystrophy


Facioscapulohumeral muscular dystrophy is a type of muscular dystrophy that preferentially weakens the skeletal muscles of the face, those that position the scapula, and those in the upper arm, overlying the humerus bone. Weakness usually develops in other areas of the body as well, such as the abdomen and next to the shin, causing foot drop. Often weakness develops on one side of the body before the other. Symptoms typically begin in early childhood and become noticeable in the teenage years, with 95% of affected individuals manifesting disease by age 20 years. Non-muscular manifestations of FSHD include hearing loss and blood vessel abnormalities in the back of the eye.
FSHD is caused by complex genetic changes that lead to failure to adequately turn off, or repress, the DUX4 gene. In those without FSHD, DUX4 is turned on, or expressed, in early human development and later repressed in mature tissues. Different mutations can cause DUX4 to be abnormally expressed, the most common being deletion of DNA in the region surrounding DUX4. This mutation is termed "D4Z4 contraction" and defines FSHD type 1, making up 95% of FSHD cases. FSHD due to other mutations is classified as FSHD type 2. Regardless of which mutation is present, disease can only result if the individual has a 4qA allele, which is a common variation in the DNA next to DUX4. Up to 30% of FSHD cases are due to a new mutation, which then is able to be passed on to children. FSHD1 follows an autosomal dominant inheritance pattern, meaning each child of an affected individual has a 50% chance of also being affected. How DUX4 expression causes muscle damage is unclear. Expression of DUX4 gene produces DUX4 protein, whose function is to modulate hundreds of other genes, many of which are involved in muscle function. Diagnosis is by genetic testing.
There is no cure for FSHD. No pharmaceuticals have proven effective for altering the disease course. Symptoms can be addressed with physiotherapy, bracing, and orthopedic surgery. Surgical fixation of the scapula to the thorax is effective in reducing shoulder symptoms in select cases. FSHD is the third most common genetic disease of skeletal muscle, affecting 1 in 8,333 to 1 in 15,000 people. Prognosis is extremely variable, with many never facing significant limitations, although up to 20% of affected individuals become severely disabled, requiring use of a wheel chair or mobility scooter. Life expectancy is generally not affected, except in rare cases of respiratory insufficiency.
The first description of an individual with FSHD is an autopsy report from 1852, although FSHD wasn't distinguished as a disease until the 1870s and 1880s when French physicians Landouzy and Dejerine followed a family affected by it; thus FSHD is sometimes referred to as Landouzy–Dejerine muscular dystrophy. In 1991, the association of most cases with the tip of chromosome 4 was established, which was discovered to be due to [|D4Z4 contraction] in 1993. DUX4 was discovered in 1999, but it wasn't until 2010 that the genetic mechanism causing its expression was elucidated. In 2012, the predominant mutation of FSHD2 was discovered. In 2014, researchers published the first proposed pathophysiology definition of the disease and four viable therapeutic targets for possible intervention points.

Signs and symptoms

Muscles of the face, shoulder girdle, and upper arm are classically affected, although these muscles can be spared and other muscles usually are affected. Distribution and degree of muscle weakness is extremely variable, even between identical twins. Individual muscles can weaken while adjacent muscles remain healthy. Muscle weakness usually becomes noticeable on one side of the body and not the other, a hallmark of the disease. The right shoulder muscles are more often affected than the left shoulder muscles, independent of handedness. Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee. Symptoms most commonly appear in teenage or early adult years, although infantile onset, adult onset, and absence of symptoms despite having the causal genetics also occur. Long static phases, in which no progression is apparent, is not uncommon. FSHD1 and FSHD2 have similar signs and symptoms, although very large D4Z4 deletions in FSHD1 are more strongly associated with infantile onset, progressive hearing loss, retinal disease, and various rare manifestations.

Face and shoulder

Weakness typically begins in the muscles of the face. The muscles surrounding the eyes are commonly affected, which can result in sleeping with eyelids open. The muscle surrounding the mouth is also commonly affected, resulting in inability to pucker the lips or whistle. There can be difficulty pronouncing the letters M, B, and P, or facial expressions that appear diminished, depressed, angry, or fatigued. After the facial weakness, weakness usually develops in the muscles of the upper torso, especially those connecting shoulder girdle to the thorax. The upper trapezius fibers often are spared. The scapulas become downwardly rotated and protracted, resulting in winged scapula and sloping shoulders. In advanced cases, the scapula appears to "herniate" up and over the rib cage. A common complaint is difficulty working with the arms overhead. The rotator cuff muscles are usually spared, even late in the disease course. Another commonly affected upper torso muscle is the pectoralis major muscle, particularly the sternocostal portion, atrophy of which can contribute to a prominent horizontal anterior axillary fold.

Upper arm and lower body

After facial and upper torso weakness, weakness can "descend" to the upper arms and the pelvic girdle. The forearms are usually spared, resulting in an appearance some compare to the fictional character Popeye. Sometimes, the weakness is observed to "skip" the pelvis and involve the tibialis anterior, causing foot drop. Weakness can also occur in the abdominal muscles, which can manifest as a protuberant abdomen, lumbar hyperlordosis, the inability to do a sit-up, or the inability to turn from one side to the other while lying down. The lower fibers of the rectus abdominis muscle are more often affected than the upper fibers, manifesting as a positive Beevor's sign. Weakness in the legs can manifest as difficulty walking or hips held in slight flexion. In advanced cases, almost any muscle can become involved, such as neck extensor muscle weakness causing head droop.

Muscle involvement from MRI perspective

Magnetic resonance imaging has shown muscle damage that doesn't cause obvious symptoms. MRI shows the teres major muscle to be affected in 80% of cases, and the semimembranosus muscle, part of the hamstrings, to be commonly affected. Also, MRI shows that the rectus femoris is more often affected than the other muscles of the quadriceps, the medial gastrocnemius is more often affected than the lateral gastrocnemius, and the iliopsoas muscle is very often spared.

Non-musculoskeletal

The most common non-musculoskeletal manifestation of FSHD is mild retinal blood vessel abnormalities, such as telangiectasias or microaneurysms, with one study placing the incidence at 50%. These abnormal blood vessels generally do not affect vision or health, although a severe form of it mimics Coat's disease, a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions. High-frequency hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population. Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-bound patients. However, ventilator support is needed in only 1% of cases.

Genetics

The genetics of FSHD are complex, culminating in abnormal expression of the DUX4 gene. In those without FSHD, DUX4 is expressed during embryogenesis and, at some point, becomes repressed in all tissues except the testes. In FSHD, there is inadequate repression of DUX4, allowing ectopic production of DUX4 protein in muscles, causing muscle damage. Two genetic elements are required for inadequate repression of DUX4. First, there must be a mutation that causes hypomethylation of the DNA surrounding DUX4, allowing transcription of DUX4 into messenger RNA. Several mutations cause hypomethylation, upon which FSHD is subclassified into FSHD type 1 and FSHD type 2.
The second genetic element needed is an allele downstream to DUX4 that allows stability to DUX4 mRNA by providing a polyadenylation sequence, which allows DUX4 mRNA to persist long enough to be translated into DUX4 protein, the causal agent of muscle damage. The allele that allows stability to DUX4 mRNA is called a 4qA allele, which is a haplotype polymorphism. The 4qB allele does not have a polyadenylation sequence.

DUX4 and the D4Z4 repeat array

DUX4 resides within the D4Z4 macrosatellite repeat array, a series of tandemly repeated DNA segments in the subtelomeric region of chromosome 4. Each D4Z4 repeat is 3.2 kilobase pairs long and is the site of epigenetic regulation, containing both heterochromatin and euchromatin structures. In FSHD, the heterochromatin structure is lost, becoming euchromatin. The name "D4Z4" is derived from an obsolete nomenclature system used for DNA segments of unknown significance during the human genome project: D for DNA, 4 for chromosome 4, Z indicates it is a repetitive sequence, and 4 is a serial number assigned based on the order of submission.
D4Z4 regulatory element transcripts are reported to de-repress DUX4 expression. Their transcription starts at the non-deleted element. Some transcripts might be degraded in areas to produce si-like small RNAs.
DUX4 consists of three exons. Exons 1 and 2 are in each repeat. Exon 3 in the pLAM region telomeric to the last partial repeat.

FSHD1

FSHD involving deletion of D4Z4 repeats is classified as FSHD1, which accounts for 95% of FSHD cases. Typically, chromosome 4 includes between 11 and 150 repetitions of D4Z4. In FSHD1, there are 1–10 repetitions of D4Z4. The number of repeats roughly inversely correlates with disease severity. Namely, those with 1 - 3 repeats are more likely to have severe, atypical, and early onset disease; those with 4 - 7 repeats have moderate disease that is highly variable; and those with 8 - 10 repeats tend to have the mildest presentations, sometimes with no symptoms. D4Z4 contraction causes D4Z4 hypomethylation, allowing DUX4 transcription. Deletion of the entire D4Z4 repeat array does not result in FSHD because then there are no complete copies of DUX4 to be expressed, although other birth defects result. Inheritance is autosomal dominant, although up to one-third of the cases appear to be from de novo mutations.
The subtelomeric region of chromosome 10q contains a tandem repeat structure highly homologous to 4q35. The repeats of 10q are termed "D4Z4-like" repeats. Because 10q usually lacks a polyadenylation sequence, it is generally not implicated in disease, except in the instance of chromosomal rearrangements between 4q and 10q leading to 4q D4Z4 contraction, or the other instance of transfer of a 4q D4Z4 repeat and polyadenylation signal onto 10q.

FSHD2

FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases. About 80% of FSHD2 cases are due to deactivating mutations in the gene SMCHD1 on chromosome 18, a gene responsible for DNA methylation. SMCHD1 deactivation results in hypomethylation of the D4Z4 repeat array. Another cause of FSHD2 is mutation in DNMT3B, which also plays a role in DNA methylation. As of 2020, early evidence indicates that a third cause of FSHD2 is mutation in both copies of the LRIF1 gene, which encodes the protein ligand-dependent nuclear receptor-interacting factor 1. LRIF1 is known to interact with the SMCHD1 protein. As of 2019, there are presumably additional mutations at other unidentified genetic locations that can cause FSHD2. Once hypomethylation leads to DUX4 expression in FSHD2, the molecular events are indistinguishable from FSHD1.
Mutation of a single allele of SMCHD1 or DNMT3B can cause disease. Mutation of both copies LRIF1 has been tentatively shown to cause disease in a single person as of 2020. As in FSHD1, a 4qA allele must be present for disease to result. However, unlike the D4Z4 array, the genes implicated in FSHD2 are not in proximity with the 4qA allele, and so they are inherited independently from the 4qA allele, resulting in a digenic inheritance pattern. For example, one parent without FSHD can pass on an SMCHD1 mutation, and the other parent, also without FSHD, can pass on a 4qA allele, bearing a child with FSHD2.

Two ends of a disease spectrum

Initially, FSHD1 and FSHD2 were described as separate diseases. However, it seems that the two are both are risk factors for disease, and not rarely do both contribute to disease in the same individual.
In those with FSHD2, although they have a 4qA allele with adjacent D4Z4 repeat number greater than 10, it is often still less than 17, suggesting that a large number of D4Z4 repeats can prevent the effects of an SMCHD1 mutation. Further studies need to be done to determine the upper limit of D4Z4 repeats in which FSHD2 can occur.
In those with a 4qA allele and 10 or fewer repeats, an additional SMCHD1 mutation has shown to worsen disease, classifying them as both FSHD1 and FSHD2. In these FSHD1/FSHD2 individuals, the methylation pattern of the D4Z4 repeat array resembles that seen in FSHD2. This combined FSHD1/FSHD2 presentation is most common in those with 9 - 10 repeats, and is seldom found in those with 8 or less repeats. The relative abundance of SMCHD1 mutations in the 9 - 10 repeat group is likely because a sizable portion of the general population has 9 - 10 repeats with no disease, yet with the additive effect of an SMCHD1 mutation, symptoms develop and a diagnosis is made. In those with 8 or fewer repeats, symptoms are more likely than in those with 9 - 10 repeats, leading to diagnosis regardless of an additional SMCHD1 mutation.
The apparent frequency of FSHD1/FSHD2 cases in the 9 - 10 repeat range, combined with the FSHD2-like methylation pattern, suggest the 9 - 10 repeat size to be an overlap zone between FSHD1 and FSDH2.

Pathophysiology

As of 2020, there seems to be a consensus that aberrant expression of DUX4 in muscle is the cause of FSHD. DUX4 is expressed in extremely small amounts, detectable in 1 out of every 1000 immature muscle cells, which appears to increase after myoblast maturation, in part because the cells fuse as they mature, and a single nucleus expressing DUX4 can provide DUX4 protein to neighboring nuclei from fused cells.
It remains an area of active research how DUX4 causes muscle damage. DUX4 protein is a transcription factor that regulates many other genes. Some of these genes are involved in apoptosis, such as p53, p21, MYC, and β-catenin. It seems that DUX4 makes muscle cells more prone to apoptosis, although details of the mechanism are still unknown and contested. Other DUX4 regulated genes are involved in oxidative stress, and it seems that DUX4 expression lowers muscle cell tolerance of oxidative stress. Variation in the ability of individual muscles to handle oxidative stress could partially explain the muscle involvement patterns of FSHD. DUX4 downregulates many genes involved in muscle development, including MyoD, myogenin, desmin, and PAX7. DUX4 has shown to reduce muscle cell proliferation, differentiation, and fusion. Estrogen seems to play a role on in modifying DUX4 effects on muscle differentiation, which could explain why females are less affected than males. DUX4 regulates a few genes that are involved in RNA quality control, and DUX4 expression has been shown to cause accumulation of RNA with subsequent apoptosis.
The cellular hypoxia response has been reported in a single study to be the main driver of DUX4-induced muscle cell death. The hypoxia-inducible factors are upregulated by DUX4, possibly causing pathologic signaling leading to cell death.
Another study found that DUX4 expression in muscle cells led to the recruitment and alteration of fibrous/fat progenitor cells, which helps explain why muscles become replaced by fat and fibrous tissue.

Diagnosis

Genetic testing

Genetic testing is the gold standard for FSHD diagnosis, as it is the most sensitive and specific test available. FSHD1 is likely if D4Z4 array length is shortened and an adjoining 4qA allele is present. Since the early 2000s, D4Z4 array length was assessed by restriction fragment length polymorphism analysis, which involves digesting the DNA with restriction enzymes and analyzing resulting restriction fragment lengths with southern blot. The restriction enzyme EcoRI is used to isolate the D4Z4 repeat array. However, EcoRI also isolates the homologous region of chromosome 10q. 10q D4Z4-like repeats contain the restriction site cut by restriction enzyme BlnI, so BlnI digestion is used to distinguish between 4q and 10q sequences. Sometimes 4q or 10q will have a combination of D4Z4 and D4Z4-like repeats due to DNA exchange between 4q and 10q, which makes analysis difficult. A 4q EcoRI restriction fragment length less than 38 kilobases is considered shortened, consistent with FSHD1. In 2020, optical mapping became available for measuring D4Z4 array length, which is more precise and less labor intensive than southern blot. The longer the EcoRI restriction fragment length, the more D4Z4 repeat units there are. The below equation is used to calculate the number of D4Z4 units.
Next-generation sequencing is not useful for diagnosing FSHD1, because the long D4Z4 repeats are not sequenceable by NGS.
If genetic testing for FSHD1 is negative, FSHD2 genetic testing is done. FSHD2 is likely if there is a lack of methylation at 4q35 and at least one 4qA allele is present. NGS can be used to detect an SMCHD1 mutation, which is usually present in FSHD2.

Alternative testing

When cost is prohibitive or a diagnosis of FSHD is not suspected as the cause of symptoms, patients and doctors may rely on one or more of the following tests, all of which are less sensitive and less specific than genetic testing.
The prevalence of FSHD ranges from 1 in 8,333 to 1 in 15,000. The Netherlands reports a prevalence of 1 in 8,333, after accounting for the undiagnosed. The prevalence in the United States is commonly quoted as 1 in 15,000.
After genetic testing became possible in 1992, average prevalence was found to be around 1 in 20,000, a large increase compared to before 1992. However, 1 in 20,000 is likely an underestimation, since many with FSHD have mild symptoms and are never diagnosed, or they are siblings of affected individuals and never seek diagnosis.
Race and ethnicity have not been shown to affect FSHD incidence or severity.
Although the inheritance of FSHD shows no predilection for biological sex, the disease manifests less often in women, and even when it manifests in women, they on average are less severely affected than affected males. Estrogen has been suspected to be a protective factor that accounts for this discrepancy. One study found that estrogen reduced DUX4 activity. However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression wasn't different through periods of hormonal changes, such as menarche, pregnancy, and menopause.

History

The first description of a person with FSHD in medical literature appears in an autopsy report by Jean Cruveilhier in 1852. In 1868, Duchenne published his seminal work on Duchenne muscular dystrophy, and as part of its differential was a description of FSHD. First in 1874, then with a more commonly cited publication in 1884, and again with pictures in 1885, the French physicians Louis Landouzy and Joseph Dejerine published details of the disease, recognizing it as a distinct clinical entity, and thus FSHD is sometimes referred to as Landouzy Dejerine disease. In their paper of 1886, Landouzy and Dejerine drew attention to the familial nature of the disorder and mentioned that four generations were affected in the kindred that they had investigated. Formal definition of FSHD's clinical features didn't occur until 1952 when a large Utah family with FSHD was studied. Beginning about 1980 an increasing interest in FSHD led to increased understanding of the great variability in the disease and a growing understanding of the genetic and pathophysiological complexities. By the late 1990s, researchers were finally beginning to understand the regions of chromosome 4 associated with FSHD.
Since the publication of the unifying theory in 2010, researchers continued to refine their understanding of DUX4. With increasing confidence in this work, researchers proposed the first a consensus view in 2014 of the pathophysiology of the disease and potential approaches to therapeutic intervention based on that model.
Over the years, FSHD has, at various times, been referred to as:

Past pharmaceutical development

Multiple pharmaceuticals have failed to show efficacy.
In 1991 the FSHD Society was founded by two individuals with FSHD, Daniel Perez and Stephen Jacobsen. The FSHD Society raised funding to provide seed grants for FSHD research, advocated for the field to standardize the name of the disease as facioscapulohumeral muscular dystrophy and FSHD, and co-wrote the MD-CARE Act, passed into law in 2001, which for the first time mandated federal resources, including National Institutes of Health funding, for all muscular dystrophies. The FSHD Society has grown into the world's largest grassroots organization advocating for patient education and scientific and medical research.

FSHD Foundation

In 2007 the FSHD Global Research Foundation was established to increase the amount of funding available to research bodies. The Foundation has identified 13 priority areas of interest for FSHD research.

FSHD-EUROPE

In 2009 the FSHD-EUROPE was founded by European associations.

Research directions

Based on the consensus model of pathophysiology, researchers propose four approaches for therapeutic intervention:
  1. enhance the epigenetic repression of the D4Z4
  2. target the DUX4 mRNA, including altering splicing or polyadenylation;
  3. block the activity of the DUX4 protein
  4. inhibit the DUX4-induced process, or processes, that leads to pathology.

    Current pharmaceutical development

Ways of measuring the disease are important for assessing the efficacy of drugs in clinical trials.