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Facioscapulohumeral muscular dystrophy (FSHMD, FSHD or FSH), which is also known as Landouzy-Dejerine,[2] is an autosomal dominant form of muscular dystrophy that initially affects the skeletal muscles of the face (facio), scapula (scapulo) and upper arms (humeral). It is the third most common genetic disease of skeletal muscle. Symptoms may develop in early childhood and are usually noticeable in the teenage years with 95% of affected individuals manifesting disease by age 20 years. A progressive skeletal muscle weakness usually develops in other areas of the body as well; often the weakness is asymmetrical. Life expectancy is normal, but up to 15% of affected individuals become severely disabled and eventually must use a wheel chair. Non-muscular symptoms frequently associated with FSHD include subclinical sensorineural hearing loss and retinal telangectasias.
FSHD was first described in 1884 by French physicians Louis Landouzy and Joseph Dejerine. 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.[4] 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.[5]
FSHD is also known by the following names:
The exact pathophysiology of FSHD remains unknown as of March 2007. Muscle histologic changes are nonspecific for the muscle wasting. There is evidence of early inflammatory changes in the muscle, but reported responses to high dose open labeled corticosteroid treatment have been negative. Animal studies of anabolic effects of beta adrenergic agonists on models of muscle wasting led to an open trial of albuterol (a beta adrenergic agonist) in which limited preliminary results support an improvement of muscle mass and strength in FSHD. Preliminary studies of muscle cultures suggest an increased sensitivity to oxidative stress, but require further exploration.
More than 95% of cases of FSHD are associated with the deletion of integral copies of a tandemly repeated 3.2kb unit (D4Z4 repeat) at the subtelomeric region 4q35 of the Human genome of which a normal chromosome will include between 11-150 repetitions of D4Z4.[5] There are both heterochromatin and euchromatin structures within D4Z4 and one putative gene called DUX4[6].[5] Inheritance is autosomal dominant, though up to one-third of the cases appear to be the result of de novo (new) mutations. The heterochromatin is specifically lost in the deletions of FSHD while the euchromatin structures remain.[5] If the entire region is removed, there are birth defects, but no specific defects on skeletal muscle. Individuals appear to require the existence of 11 or fewer repeat units to be at risk for FSHD. Though the nature of the DNA mutation is known, it has not been possible to identify a gene or mechanism that causes FSHD and a novel position effect has been postulated to explain the disease phenotype. In addition, a few cases of FSHD are the result of rearrangements between subtelomeric chromosome 4q and a subtelomeric region of 10q that contains a tandem repeat structure highly homologous (95%) to 4q35. Disease occurs when the translocation results in a critical loss of tandem repeats to the 4q site. Finally, there is a large family with a phenotype indistinguishable from FSHD in which no pathological changes at the 4q site or translocation of 4q-10q are found.
Since the early 2000s genetic testing that measures the size of the D4Z4 deletions on 4q35 has become the preferred mechanism for confirming the presence of FSHD. As of 2007, this test is considered highly accurate but is still performed by a limited set of labs in the US, such as Athena diagnostics under test code 405. However, because the test is expensive, patients and doctors may still rely on one or more of the following tests, all of which are far less accurate and specific than the genetic test:[7]
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