array, require specially prepared high quality and high molecular weight genomic dna (gdna) from serum, increasing cost and reducing accessibility to testing. diagram showing restriction enzyme sites used to differentiate between d4z4 repeat arrays of 4q and 10q. restriction fragment length polymorphism (rflp) analysis was the first genetic test developed and is still used as of 2020, although it is being phased out by newer methods. 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. the ecori restriction fragment is composed of three parts: 1) 5.7 kb proximal part, 2) the central, variable size d4z4 repeat array, and 3) the distal part, usually 1.25 kb. the proximal portion has a sequence of dna stainable by the probe p13e-11, which is commonly used to visualize the ecori fragment during southern blot. the name "p13e-11" reflects that it is a subclone of a dna sequence designated as cosmid 13e during the human genome project. considering that each d4z4 repeat is 3.3 kb, and the ecori fragment contains 6.9 kb of dna that is not part of the d4z4 repeat array, the number of d4z4 units can be calculated. d4z4 repeats = (ecori length - 6.9) / 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, requiring more detailed workup. sometimes d4z4 repeat array deletions can include the p13e-11 binding site, warranting use of alternate probes. assessing methylation status 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. other methylation assays have been proposed or used in research settings, including methylated dna immunoprecipitation and bisulfite sequencing, but are not routinely used in clinical practice. bisulfite sequencing, if validated, would be valuable due to it being able to use lower quality dna sources, such as those found in saliva. auxiliary testing mri showing asymmetrical involvement of various muscles in fshd other tests can support the diagnosis of fshd, although they are all less sensitive and less specific than genetic testing. nonetheless, they can rule out similar-appearing conditions. creatine kinase (ck) blood level is often ordered when muscle damage is suspected. ck is an enzyme found in muscle, leaking into the blood when muscles become damaged. in fshd, ck level is normal to mildly elevated, never exceeding five times the upper limit of normal. electromyogram (emg) measures the electrical activity in the muscle. emg can show nonspecific signs of muscle damage or irritability. nerve conduction velocity (ncv) measures the how fast signals travel along a nerve. the nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram) or needle electrodes. muscle biopsy is the surgical removal and examination of a small piece of muscle, usually from the arm or leg. microscopy and a variety of biochemical tests are used for examination. findings in fshd are nonspecific, such as presence of white blood cells or variation in muscle fiber size. this test is rarely indicated. muscle mri is sensitive for detecting muscle damage, even in mild cases. because of the particular muscle involvement patterns of fshd, mri can help differentiate fshd from other muscle diseases, directing genetic testing. differential diagnosis included in the differential diagnosis of fshd are limb-girdle muscular dystrophy (especially calpainopathy), scapuloperoneal myopathy, 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 the suggest an alternative diagnosis are contractures, respiratory insufficiency, weakness of muscles controlling eye movement, and weakness of the tongue or throat. management no intervention has proven to significantly slow progression of weakness or improve strength. screening and monitoring of complications the american academy of neurology (aan) recommends several medical tests to detect complications of fshd. a dilated eye exam to look for retinal abnormalities is recommended in those newly diagnosed with fshd; for those with large d4z4 deletions, an evaluation by a retinal specialist is recommended yearly. a hearing test is recommended for individuals with early-onset fshd prior to starting school, or for any other fshd-affected individual with symptoms of hearing loss. pulmonary function testing (pft) is recommended in those newly diagnosed to establish baseline pulmonary function, and recurrently for those with pulmonary insufficiency symptoms or risks. routine screening for heart conditions, such as through an electrocardiogram (ekg) or echocardiogram (echo), is considered unnecessary in those without symptoms of heart disease. physical and occupational therapy aerobic exercise has been shown to reduce chronic fatigue and decelerate fatty infiltration of muscle in fshd. the ann recommends that people with fshd engage in low-intensity aerobic exercise to promote energy levels, muscle health, and bone health. moderate-intensity strength training appears to do no harm, although it has not been shown to be beneficial. 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. braces are often used to address muscle weakness. scapular bracing can improve scapular positioning, which improves shoulder function, although it is often deemed as ineffective or impractical. ankle-foot orthoses can improve walking, balance, and quality of life. pharmacologic management no pharmaceuticals have definitively proven effective for altering the disease course. although a few pharmaceuticals have shown improved muscle mass in limited respects, they did not improve quality of life, and the aan recommends against their use for fshd. reconstructive surgery scapular winging is amenable to surgical correction, namely operative scapular fixation. scapular fixation is restriction and stabilization of the position of the scapula, putting it in closer apposition to the rib cage and reducing winging. absolute restriction of scapular motion by fixation of the scapula to the ribs is most commonly reported. this procedure often involves inducing bony fusion, called arthrodesis, between the scapula and ribs. names for this include scapulothoracic fusion, scapular fusion, and scapulodesis. this procedure increases arm active range of motion, improves arm function, decreases pain, and improves cosmetic appearance. 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. the aan states that scapular fixation can be offered cautiously to select patients after balancing these benefits against the adverse consequences of surgery and prolonged immobilization. another form of operative scapular fixation is scapulopexy. "scapulo-" refers to the scapula bone, and "-pexy" is derived from the greek root "to bind." some versions of scapulopexy accomplish essentially the same result as scapulothoracic fusion, but instead of inducing bony fusion, the scapula is secured to the ribs with only wire, tendon grafts, or other material. some versions of scapulopexy do not completely restrict scapular motion, examples including tethering the scapula to the ribs, vertebrae, or other scapula. scapulopexy is considered to be more conservative than scapulothoracic fusion, with reduced recovery time and less effect on breathing. however, they also seem more susceptible to long-term failure. another form of scapular fixation, although not commonly done in fshd, is tendon transfer, which involves surgically rearranging the attachments of muscles to bone. 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. 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 is a compensatory change in response to muscle weakness, correction of spinal alignment can result in further impaired muscle function. scapular winging management kinesiology tape applied across the scapulas. a cloth brace to hold the scapulas in retraction to reduce shoulder symptoms, such as collarbone pain. 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. those with large d4z4 repeat deletions (with a remaining d4z4 repeat array size of 10-20 kbp, or 1-4 repeats) are more likely to have severe and early disease, as well as non-muscular symptoms. those who have the genetic mutations of both fshd1 and fshd2 are more likely to have severe disease. it has also been observed that disease manifestation is milder when a prominent family history is present, as opposed to a new mutation. in some large families, 30% of those with the mutation do not show symptoms, and 30% of those with symptoms do not progress beyond facial and shoulder weakness. women are less likely to be symptomatic, and if symptomatic have less severe manifestations. remaining variations in disease course are attributed to unknown environmental factors. a single study found that disease course is not worsened by tobacco smoking or alcohol consumption, common risk factors for other diseases. pregnancy pregnancy outcomes are overall good in mothers with fshd; there is no difference in 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 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 definitive 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 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. 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 did not occur until 1952 when a large utah family with fshd was studied. beginning about 1980 an increasing interest in fshd led to increased