Facioscapulohumeral muscular dystrophy

Classically, weakness develops in the face, then the shoulder girdle, then the upper arm. These muscles can be spared, and other muscles usually are affected. The order of muscle involvement can cause the appearance of weakness, "descending" from the face to the legs. Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee. Otherwise, neither side of the body is at more risk. Classically, symptoms appear in those 15–30 years old, although adult-onset can also occur. Otherwise, FSHD1 and FSHD2 are indistinguishable on the basis of weakness. Less commonly, individual muscles rapidly deteriorate over several months. Face Weakness of the muscles of the face is the most distinguishing sign of FSHD. Difficulty swallowing is not typical, although it can occur in advanced cases, which is at least in part due to facial muscle weakness. FSHD is generally progressive, but it is not established whether facial weakness is progressive or stable throughout life. Also affected is the chest, particularly the parts of the pectoralis major muscle that connect to the sternum and ribs. The part that connects to the clavicle is less often affected. This muscle-wasting pattern can contribute to a prominent horizontal anterior axillary fold. Beyond this point, the disease does not progress further in 30% of familial cases. Weakness can also occur in the abdominal muscles and paraspinal muscles, which can manifest as a protuberant abdomen and lumbar hyperlordosis. These abnormalities of arterioles usually 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 sensorineural hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population. Scoliosis can occur, thought to result from muscular weakness in the abdomen, hip extensors, and spine. Conversely, scoliosis can be viewed as a compensatory mechanism to weakness. Although there are reports of increased risk of cardiac arrhythmias, the consensus is that the heart is unaffected. ==Genetics==

of DUX4 protein full-length (FL), with short (S) version indicated The genetics of FSHD are complex. The DUX4 gene is the focal point of FSHD genetics. Normally, full-length DUX4 protein (DUX4-fl) is expressed during early embryogenesis, in testicular tissue of adults, and the thymus; in all other tissues, it is repressed. Each D4Z4 repeat is 3.3 kilobase pairs (kb) long and is the site of epigenetic regulation, containing both heterochromatin and euchromatin structures. In FSHD, the heterochromatin structure is lost, becoming euchromatin, Because 10q usually lacks a polyadenylation sequence, it is usually not implicated in disease. However, chromosomal rearrangements can occur between 4q and 10q repeat arrays, and involvement in disease is possible if a 4q D4Z4 repeat and polyadenylation signal are transferred onto 10q, or if rearrangement causes FSHD1. D4Z4 repeat array types are subclassified into 4qA and 4qB alleles, with only 4qA alleles causing disease. 4qA alleles are defined by a specific sequence of DNA immediately downstream to the D4Z4 repeat array: a 260 base pair region named pLAM, followed by a 6,200 base pair beta satellite region. 4qA and 4qB alleles, together, can be subdivided into at least 17 types, based on the DNA upstream from the D4Z4 repeat array, the presence/absence of restriction enzyme sites within D4Z4, the size of the last D4Z4 repeat element, and the DNA present downstream to the D4Z4 repeat array. A polyadenylation signal is within exon 3. Because exon 3 and its containing polyadenylation signal are not contained within each D4Z4 repeat, only the last D4Z4 repeat of a D4Z4 repeat array can encode a stable mRNA transcript to produce the DUX4 protein. These transcripts can be spliced in several ways to form mature RNA. One of these transcripts encodes only a portion of DUX4 protein, termed DUX4-s (DUX4-short). One proposed mechanism is that DBE-T leads to the recruitment of the trithorax-group protein Ash1L, an increase in H3K36me2-methylation, and ultimately de-repression of 4q35 genes. FSHD1 FSHD involving deletion of D4Z4 repeats (termed 'D4Z4 contraction') on 4q is classified as FSHD1, which accounts for 95% of FSHD cases. As of 2019, more detailed studies are needed to show definitively whether or not anticipation occurs. If anticipation does occur in FSHD, the mechanism is different than that of trinucleotide repeat disorders, since D4Z4 repeats are much larger than trinucleotide repeats, an underabundance of repeats (rather than overabundance) causes disease, and the repeat array size in FSHD is stable across generations. FSHD2 FSHD with a D4Z4 array repeat size of 11 or greater is classified as FSHD2, responsible for 5% of FSHD cases. Another cause of FSHD2 is mutation in DNMT3B (DNA methyltransferase 3B). Mutations in DNMT3B can also cause ICF syndrome. LRIF1 is known to interact with the SMCHD1 protein. Two ends of a disease spectrum FSHD1 and FSHD2 have traditionally been viewed as separate entities with distinct genetic causes (although the downstream genetic mechanisms merge). Alternatively, the genetic causes of FSHD1 and FSHD2 can be viewed as risk factors, each contributing to an FSHD disease spectrum. For example, in those with FSHD2, although they have do not have a 4qA allele with D4Z4 repeat number less than 11, they still have one less than 30 (shorter than the upper limit seen in the general population), suggesting that a large number of D4Z4 repeats can prevent the effects of an SMCHD1 mutation. A combined FSHD1/FSHD2 presentation is most common in those with 9–10 repeats. A possible explanation is that a sizable portion of the general population has 9–10 repeats with difficult-to-detect or no disease. The additive effect of an SMCHD1 mutation may be severe enough to make a diagnosis. The 9–10 repeat size can be considered as an overlap zone between FSHD1 and FSHD2. ==Pathophysiology==

Molecular As of 2020, there seems to be a consensus that aberrant expression of DUX4 in muscle is the cause of FSHD. How the DUX4 protein causes muscle damage remains an area of active research. 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, and indeed it seems that DUX4 protein makes muscle cells more prone to apoptosis. Other DUX4 protein-regulated genes are involved in oxidative stress, and it seems that DUX4 expression lowers muscle cell tolerance of oxidative stress. Variations in individual muscles' ability to tolerate oxidative stress could partially explain the muscle involvement patterns of FSHD. DUX4 protein downregulates many genes involved in muscle development, including MyoD, myogenin, desmin, and PAX7, and indeed DUX4 expression has shown to reduce muscle cell proliferation, differentiation, and fusion. DUX4 protein regulates a few genes that are involved in RNA quality control, and indeed DUX4 expression has been shown to cause accumulation of RNA with subsequent apoptosis. Estrogen seems to play a role in modifying DUX4 protein effects on muscle differentiation, which could explain why females are less affected than males, although it remains unproven. 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. Muscle histology s. Visible is inflammation and fibrosis, as well as muscle fiber shape change, death, and regeneration. Unlike other muscular dystrophies, early muscle biopsies show only mild degrees of fibrosis, muscle fiber hypertrophy, and displacement of nuclei from myofiber peripheries (central nucleation). Muscle involvement pattern Why certain muscles are preferentially affected in FSHD remains unknown. Multiple patterns of involvement are observed in FSHD, possibly hinting at underlying pathophysiology. Individual muscles can weaken while adjacent muscles remain strong. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, a pattern also seen in Poland syndrome and hereditary neuralgic amyotrophy; this could reflect a genetic, developmental/anatomic, or functional-related mechanism. Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise • A single MRI study shows the teres major muscle to be commonly affected. • The semimembranosus muscle, part of the hamstrings, is commonly affected, deemed by one author to be "the most frequently and severely affected muscle." • Of the quadriceps muscles, the rectus femoris is preferentially affected • Of the gastrocnemius, the medial section is preferentially affected; • The iliopsoas, a hip flexor muscle, is very often spared. Retinopathy Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are commonly found in FSHD. Abnormalities of the capillaries and venules are not observed. One theory for why the arterioles are selectively affected is that they contain smooth muscle. The degree of D4Z4 contraction correlates to the severity of tortuosity of arterioles. It has been hypothesized that retinopathy is due to DUX4-protein-induced modulation of the CXCR4–SDF1 axis, which has a role in endothelial tip cell morphology and vascular branching. == Diagnosis ==

FSHD can be presumptively diagnosed in many cases based on signs, symptoms, and/or non-genetic medical tests, especially if a first-degree relative has genetically confirmed FSHD. Genetic testing Genetic testing is the gold standard for FSHD diagnosis, as it is the most sensitive and specific test available. Assessing D4Z4 length Measuring D4Z4 length is technically challenging since the D4Z4 repeat array consists of long, repetitive elements. For example, NGS is not useful for assessing D4Z4 length, because it breaks DNA into fragments before reading them, and it is unclear from which D4Z4 repeat each sequenced fragment came. Molecular combing is also available for assessing D4Z4 array length. These methods, which physically measure the size of the D4Z4 repeat array, require specially prepared high-quality and high molecular weight genomic DNA (gDNA) from serum, increasing cost and reducing accessibility to testing. Restriction fragment length polymorphism (RFLP) analysis was the first genetic test developed and is still used as of 2020, although newer methods are poised to supplant this test. It involves dicing the DNA with restriction enzymes and sorting the resulting restriction fragments by size using southern blot. The restriction enzymes EcoRI and BlnI are commonly used. EcoRI isolates the 4q and 10q repeat arrays, and BlnI dices the 10q sequence into small pieces, allowing 4q to be distinguished. Considering that each D4Z4 repeat is 3.3 kb, and the EcoRI fragment contains about 5 kb of DNA that is not part of the D4Z4 repeat array, the number of D4Z4 units can be calculated. :D4Z4 repeats = (EcoRI length - 5) / 3.3 Sometimes 4q or 10q will have a combination of D4Z4 and D4Z4-like repeats due to DNA exchange between 4q and 10q, which can yield erroneous results that require a more detailed workup. Assessing methylation status The methylation status of 4q35 is traditionally assessed after FSHD1 testing is negative. Methylation sensitive restriction enzyme (MSRE) digestion showing hypomethylation has long been considered diagnostic of FSHD2. US is effective at identifying fatty infiltration or scarring of muscles due to FSHD, manifesting as increased echogenicity (appearing brighter on ultrasound imaging). mitochondrial myopathy, Pompe disease, and polymyositis. Calpainopathy and scapuloperoneal myopathy, like FSHD, present with scapular winging. Features that suggest FSHD are facial weakness, asymmetric weakness, and lack of benefit from immunosuppression medications. Features that suggest an alternative diagnosis are contractures, respiratory insufficiency, weakness of muscles controlling eye movement, and weakness of the tongue or throat. == Management ==

No pharmacologic treatment has proven to slow the progression of weakness significantly or improve strength meaningfully. Physical activity in general might slow disease progression in the legs. Physical therapy can address specific symptoms; there is no standardized protocol for FSHD. Anecdotal reports suggest that appropriately applied kinesiology tape can reduce pain. Occupational therapy can be used for training in activities of daily living (ADLs) and to help adapt to new assistive devices. Cognitive behavioral therapy (CBT) has been shown to reduce chronic fatigue in FSHD, and it also decelerates fatty infiltration of muscle when directed towards increasing daily activity. Ankle-foot orthoses can improve walking, balance, and quality of life. Pharmacologic management No pharmaceuticals have definitively proven effective for altering the disease course. Active range of motion of the arm increases most in the setting of severe scapular winging with an unaffected deltoid muscle; however, passive range of motion decreases. In other words, the patient gains the ability to slowly raise their arms to 90+ degrees, but they lose the ability to "throw" their arm up to a full 180 degrees. Scapulopexy is considered to be more conservative than scapulothoracic fusion, with reduced recovery time and less effect on breathing. Examples include pectoralis major transfer and the Eden–Lange procedure. Various other surgical reconstructions have been described. Upper eyelid gold implants have been used for those unable to close their eyes. Drooping lower lip has been addressed with plastic surgery. Ability to smile can theoretically be restored with a tendon transfer, with donors such as a portion of the temporalis muscle, although evidence is lacking in FSHD. Select cases of foot drop can be surgically corrected with tendon transfer, in which the tibialis posterior muscle is repurposed as a tibialis anterior muscle, a version of this being called the Bridle procedure. Severe scoliosis caused by FSHD can be corrected with spinal fusion; however, since scoliosis might be a compensatory change in response to muscle weakness, correction of spinal alignment can result in further impaired muscle function. File:FSHD Kinesiology Tape.png|Kinesiology tape applied across the scapulas File:Retraction brace FSHD white.png|A cloth brace to hold the scapulas in retraction to reduce shoulder symptoms, such as collarbone pain File:Before and after Scapula-to-scapula scapulopexy FSHD.png|Scapula-to-scapula scapulopexy, pre- and post-operation. The scapulas are tethered together into a retracted position with an Achilles tendon graft, which, in this case, rendered the rhomboid major muscles distinguishable. == Prognosis ==

Genetics partially predicts prognosis. In some large families, 30% of those with the mutation had no noticeable symptoms, and 30% of those with symptoms did not progress beyond facial and shoulder weakness. Pregnancy Pregnancy outcomes are overall good in mothers with FSHD; there is no difference in the rate of preterm labor, rate of miscarriage, and infant outcomes. However, weakness can increase the need for assisted delivery. A single review found that weakness worsens, without recovery, in 12% of mothers with FSHD during pregnancy, although this might be due to weight gain or deconditioning. == Epidemiology ==

The prevalence of FSHD ranges from 1 in 8,333 to 1 in 15,000. The prevalence in the United States is commonly quoted as 1 in 15,000. However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression was not 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. Alternate and historical names for FSHD include the following: • facioscapulohumeral disease Compounds were trialed with goals of increasing muscle mass, decreasing inflammation, or addressing provisional theories of disease mechanism. • Oral albuterol, a β2 agonist, on the basis of its anabolic properties. Although it improved muscle mass and certain measures of strength in those with FSHD, it did not improve global strength or function. Interestingly, β2 agonists were later shown to reduce DUX4 expression. • MYO-029 (stamulumab), an antibody that inhibits myostatin, was developed to promote muscle growth. Myostatin is a protein that inhibits the growth of muscle tissue. • ACE-083, a TGF-β inhibitor, was developed to promote muscle growth. == Society and culture ==

Media • In the Amazon Video series The Man in the High Castle, Obergruppenführer John Smith's son, Thomas, is diagnosed with Landouzy–Dejerine syndrome. • In the biography Stuart: A Life Backwards, the protagonist was affected by muscular dystrophy, presumably FSHD. • Good Bad Things, an independent film about an entrepreneur afflicted with FSHD and his journey of transformation, self-acceptance and discovery. The movie premiered at the 2024 Slamdance Film Festival • The Lost Voice, a short film featuring Tristram Ingham, who lives with FSHD. Ingham used Apple's Personal Voice feature to recreate his voice and use it to read a children's book titled The Lost Voice for International Day of Persons with Disabilities in 2023. Patient and research organizations • The FSHD Society (named "FSH Society" until 2019) was founded in 1991 on the East Coast by two individuals with FSHD, Daniel Perez and Stephen Jacobsen. The FSHD Society claims to have advocated for the standardization of the disease name facioscapulohumeral muscular dystrophy and its abbreviation FSHD. One notable spokesperson for FSHD Society has been Max Adler, an actor on the TV series Glee. • Friends of FSH Research is a research-oriented nonprofit organization founded in 2004 by Terry and Rick Colella from Kirkland, Washington, after their son was diagnosed with FSHD. • The FSHD Global Research Foundation was founded in 2007 by Bill Moss in Australia, a former Macquarie Bank executive affected by FSHD. It is currently directed by Moss's daughter. Spanning multiple countries in Europe, it has launched the European Trial Network. • Chris Carrino is the radio voice of the Brooklyn Nets. He founded the Chris Carrino Foundation for FSHD, oriented towards research funding. • Madison Ferris is an American actress with FSHD who was the first wheelchair user to play a lead on Broadway. • Morgan Hoffmann is an American professional golfer. He started the Morgan Hoffmann Foundation, oriented towards research funding. • Arnold Gold (1925–2024) was a pediatric neurologist, founder of the Arnold P. Gold Foundation, and creator of white coat ceremonies. Gold focused on patient-centered care and humanism. • Argyris Loizou is a Greek Cypriot slam poet, diagnosed with facioscapulohumeral muscular dystrophy at age 20. Loizou has twice won the national Slam Championship, writing about his experiences with the condition. ==Research directions==

Pharmaceutical development After achieving consensus on FSHD pathophysiology in 2014, researchers proposed four approaches for therapeutic intervention: Results of a phase IIb clinical trial, revealed in June 2021, showed statistically significant slowing of muscle function deterioration. Further trials are pending. • Casein kinase 1 (CK1) inhibition has been identified by Facio Therapies, a Dutch pharmaceutical company, to repress DUX4 expression and is in preclinical development. Facio Therapies claims that CK1 inhibition leaves myotube fusion intact, unlike BET inhibitors, p38 MAPK inhibitors, and β2 agonists. Gene therapy Gene therapy is the administration of nucleotides to treat disease. Multiple types of gene therapy are in the preclinical stage of development for the treatment of FSHD. • Antisense therapy utilizes antisense oligonucleotides that bind to DUX4 messenger RNA, inducing its degradation and preventing DUX4 protein production. Phosphorodiamidate morpholinos, an oligonucleotide modified to increase its stability, have been shown to reduce DUX4 and its effects selectively; however, these antisense nucleotides have poor ability to penetrate muscle. • Genome editing, the permanent alteration of genetic code, is being researched. One study attempted to use CRISPR-Cas9 to knockout the polyadenylation signal in lab dish models but was unable to demonstrate therapeutic results. Potential drug targets • Inhibition of the hyaluronic acid (HA) pathway is a potential therapy. One study found that many DUX4-induced molecular pathologies are mediated by HA signaling, and inhibition of HA biosynthesis with 4-methylumbelliferone prevented these molecular pathologies. • P300 inhibition has shown to inhibit the deleterious effects of DUX4 • BET inhibitors have been shown to reduce DUX4 expression. • Antioxidants could potentially reduce the effects of FSHD. One study found that vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation increased endurance and strength of the quadriceps, but had no significant benefit on walking performance. Further study is warranted. • Quality of life can be measured with questionnaires, such as the FSHD Health Index. or FSHD composite outcome measure (FSHD-COM). • Electrical impedance myography is being studied as a way to measure muscle damage. • Muscle MRI is useful for the assessment of all the muscles in the body. Muscles can be scored based on the degree of fat infiltration. ==References==