Facioscapulohumeral muscular dystrophy
Encyclopedia
Facioscapulohumeral muscular dystrophy (sometimes switched as faciohumeroscapular) (FSHMD, FSHD or FSH), which is also known as Landouzy-Dejerine, is a usually autosomal dominant inherited form of muscular dystrophy
(MD) that initially affects the skeletal muscles of the face (facio), scapula
(scapulo) and upper arms (humeral). While it is widely stated to be the third most common genetic disease of skeletal muscle
, a 2008 analysis of rare diseases listed FSHD as the most prevalent form of MD at 7/100,000.
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.
In more than 95% of known cases, the disease is associated with deletions of the D4Z4 repeat in the 4q35 subtelomeric region of Chromosome 4. Seminal research published in August 2010 now shows that a second mechanism is needed for FSHD, which for the first time provides a unifying theory for the underlying genetics of FSHD. The second mechanism was found to be a "toxic gain of function" of the DUX4
gene which is the first time in the history of genetic research that a "dead gene" has been found to "wake up" and cause disease.
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. 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.
FSHD is also known by the following names:
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 salbutamol
(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.
of the Human genome
of which a normal chromosome will include between 11-150 repetitions of D4Z4. There are both heterochromatin
and euchromatin
structures within D4Z4 and one putative gene called DUX4
. Inheritance is autosomal dominant, though up to one-third of the cases appear to be the result of de novo (new) mutation
s. The heterochromatin is specifically lost in the deletions of FSHD while the euchromatin structures remain. 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. .
In addition, a few cases of FSHD are the result of rearrangements between subtelomeric chromosome 4q and a subtelomeric region of 10q. This location contains a tandem repeat structure highly homologous to 4q35. Disease occurs when the translocation
results in a critical loss of tandem repeats to the 4q site.
It has been suggested that this may be due to limitations in the available tests.
undergoes a "toxic gain of function" as a result of single nucleotide polymorphisms in the region distal to the last D4Z4 repeat. According to the research, this leads to a "canonical polyadenylation
signal for transcripts derived from DUX4". This is the first time in the history of genetics in which "junk" DNA has been shown to reanimate and cause disease. The documentation of the conditions under which the DUX4 gene became reanimated answered the question of why no one whose dead gene was repeated more than 10 times ever got FSHD but only some people with fewer than 10 copies did get the disease Several organizations including the New York Times highlighted this research (See MDA, FSH Society, University of Rochester, NYT).
Dr. Francis Collins
, who oversaw the first sequencing of the Human Genome
with the National Institutes of Health
stated:
Daniel Perez, co-founder, President and CEO of the FSH Society hailed the new findings saying:
The MDA stated that:
Quoted in the University of Rochester press release, one of the report's co-authors, Silvère van der Maarel of the University of Leiden, stated that
The original identification of the D4Z4 deletions was found in 1992. This research now shows that a second mechanism is needed for FSHD to be present and that the remaining versions of the DUX4 become more active (open for transcription
) because the DNA at the tip of chromosome 4 is less tightly coiled as a result of the deletions.
(INSERM), lists a prevalence of 7/100,000 which would make FSHD the most prevalent form of Muscular Dystrophy (Duchene and Becker are listed at 5/100,000).
Symptoms:
is a compound identified in 2005/2006 by Johns Hopkinshttp://www.mdausa.org/research/060106myostatin_blocker.html. It increased muscle mass in a non-Muscular Dystrophy Mouse by up to 60% in two weeks.
inhibiting drug developed by Wyeth Pharmaceuticals
for the treatment of muscular dystrophy. Myostatin is a protein that inhibits the growth of muscle tissue, MYO-029 is a recombinant human antibody designed to bind and inhibit the activity of myostatin. A 2005/2006 study was completed by Wyeth in Collegeville, PA and included participants afflicted with FSHD. The study could not prove its efficacy.
Muscular dystrophy
Muscular dystrophy is a group of muscle diseases that weaken the musculoskeletal system and hamper locomotion. Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue.In the 1860s, descriptions of boys who...
(MD) that initially affects the skeletal muscles of the face (facio), scapula
Scapula
In anatomy, the scapula , omo, or shoulder blade, is the bone that connects the humerus with the clavicle ....
(scapulo) and upper arms (humeral). While it is widely stated to be the third most common genetic disease of skeletal muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, a 2008 analysis of rare diseases listed FSHD as the most prevalent form of MD at 7/100,000.
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
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
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.
In more than 95% of known cases, the disease is associated with deletions of the D4Z4 repeat in the 4q35 subtelomeric region of Chromosome 4. Seminal research published in August 2010 now shows that a second mechanism is needed for FSHD, which for the first time provides a unifying theory for the underlying genetics of FSHD. The second mechanism was found to be a "toxic gain of function" of the DUX4
DUX4
Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.-Gene:This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10...
gene which is the first time in the history of genetic research that a "dead gene" has been found to "wake up" and cause disease.
History
| 1900–1950 | 0 |
| 1951–1975 | 30 |
| 1976–1990 | 133 |
| 1991–1996 | 148 |
| 1997–2006 | 294 |
| data from the Entrez-Pubmed database | |
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. 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.
FSHD is also known by the following names:
- Landouzy-Dejerine
- Landouzy-Dejerine syndrome
- Erb-Landouzy-Dejerine syndrome
- Landouzy-Dejerine dystrophy or atrophy
Pathophysiology
The exact pathophysiologyPathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
of FSHD remains unknown as of March 2007. Muscle histologic
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
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
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
treatment have been negative. Animal studies of anabolic effects of beta adrenergic agonists on models of muscle wasting led to an open trial of salbutamol
Salbutamol
Salbutamol or albuterol is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It is marketed as Ventolin among other brand names....
(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.
FSHMD1A (4q35 deletion)
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 on Chromosome 4Chromosome 4 (human)
125px|rightChromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area...
of the Human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
of which a normal chromosome will include between 11-150 repetitions of D4Z4. There are both heterochromatin
Heterochromatin
Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
and euchromatin
Euchromatin
Euchromatin is a lightly packed form of chromatin that is rich in gene concentration, and is often under active transcription. Unlike heterochromatin, it is found in both cells with nuclei and cells without nuclei...
structures within D4Z4 and one putative gene called DUX4
DUX4
Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.-Gene:This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10...
. Inheritance is autosomal dominant, though up to one-third of the cases appear to be the result of de novo (new) mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s. The heterochromatin is specifically lost in the deletions of FSHD while the euchromatin structures remain. 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. .
In addition, a few cases of FSHD are the result of rearrangements between subtelomeric chromosome 4q and a subtelomeric region of 10q. This location contains a tandem repeat structure highly homologous to 4q35. Disease occurs when the translocation
Translocation
Translocation may refer to:* Chromosomal translocation, in genetics* Translocation in plants, transport of food or pesticides through phloem or xylem* Protein translocation or protein targeting, a process in protein biosynthesis...
results in a critical loss of tandem repeats to the 4q site.
FSHMD1B (unknown locus)
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.It has been suggested that this may be due to limitations in the available tests.
A Unifying Theory
On 19 August 2010, a paper entitled A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy was published in Science showing that the candidate gene DUX4DUX4
Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.-Gene:This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10...
undergoes a "toxic gain of function" as a result of single nucleotide polymorphisms in the region distal to the last D4Z4 repeat. According to the research, this leads to a "canonical polyadenylation
Polyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
signal for transcripts derived from DUX4". This is the first time in the history of genetics in which "junk" DNA has been shown to reanimate and cause disease. The documentation of the conditions under which the DUX4 gene became reanimated answered the question of why no one whose dead gene was repeated more than 10 times ever got FSHD but only some people with fewer than 10 copies did get the disease Several organizations including the New York Times highlighted this research (See MDA, FSH Society, University of Rochester, NYT).
Dr. Francis Collins
Francis Collins (geneticist)
Francis Sellers Collins , is an American physician-geneticist, noted for his discoveries of disease genes and his leadership of the Human Genome Project . He currently serves as Director of the National Institutes of Health in Bethesda, Maryland. Prior to being appointed Director, he founded and...
, who oversaw the first sequencing of the Human Genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
with the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
stated:
“If we were thinking of a collection of the genome’s greatest hits, this would go on the list,”
Daniel Perez, co-founder, President and CEO of the FSH Society hailed the new findings saying:
"This is a long-sought explanation of the exact biological workings of a disease that affects an estimated one in 14,000 or 22,100 Americans and 490,000 worldwide,” he said, adding that this discovery “creates an enormous opportunity for research to develop ways to prevent or treat FSHD.”
The MDA stated that:
"The new findings will make it easier to diagnose FSHD in someone with symptoms and predict who will develop the disease in someone without symptoms. Now, the hunt is on for which proteins or genetic instructions (RNARNARibonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
) are causing the problem for muscle tissue in FSHD."
Quoted in the University of Rochester press release, one of the report's co-authors, Silvère van der Maarel of the University of Leiden, stated that
“It is amazing to realize that a long and frustrating journey of almost two decades now culminates in the identification of a single small DNA variant that differs between patients and people without the disease. We finally have a target that we can go after.”
The original identification of the D4Z4 deletions was found in 1992. This research now shows that a second mechanism is needed for FSHD to be present and that the remaining versions of the DUX4 become more active (open for transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
) because the DNA at the tip of chromosome 4 is less tightly coiled as a result of the deletions.
Testing
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:- Creatine kinaseCreatine kinaseCreatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
(CK) level: This test measures the Creatine kinase enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
in the blood. Elevated levels of CK are related to muscle atrophy. - electromyogram (EMG): This test measures the electrical activity in the muscle
- nerve conduction velocityNerve conduction velocityNerve conduction velocity is the speed at which an electrochemical signal propagates down a neural pathway. Many things can affect this, including axon diameter, myelination, the internal resistance of the axon, and temperature. Nerve conduction velocity differs from species to species, and to a...
(NCV): This test measures the how fast signals travel from one part of a nerve to another. The nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram), and the test is only slightly uncomfortable. - muscle biopsyMuscle biopsyIn medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. A biopsy needle is usually inserted into a muscle, wherein a small amount of tissue remains. Alternatively, an "open biopsy" can be performed by obtaining the...
: Through outpatient surgery a small piece of muscle is removed (usually from the arm or leg) and evaluated with a variety of biochemical tests. Researchers are attempting to match results of muscle biopsies with DNA tests to better understand how variations in the genome present themselves in tissue anomalies.
Symptoms and prevalence
Because of the extreme variability of the disease, an authoritative and scientifically confirmed set of symptoms does not yet exist. The prevalence is widely quoted to be 1/20,000, but the exact prevalence is not known. A November 2008 report from Orpha.net, an organization backed by the Institut National de la Santé et de la Recherche MédicaleInstitut National de la Santé et de la Recherche Médicale
Institut National de la Santé et de la Recherche Médicale is a French biomedical and public health research institution.- Medical research organisation :...
(INSERM), lists a prevalence of 7/100,000 which would make FSHD the most prevalent form of Muscular Dystrophy (Duchene and Becker are listed at 5/100,000).
Symptoms:
- Facial muscle weakness (eyelid drooping, inability to whistle, decreased facial expression, depressed or angry facial expression, difficulty pronouncing the letters M, B, and P)
- Shoulder weakness (difficulty working with the arms raised, sloping shoulder)
- Hearing loss
- Abnormal heart rhythm
- Unequal weakening of the biceps, triceps, deltoids, and lower arm muscles
- Loss of strength in stomach muscles and eventual progression to the legs
- Foot dropFoot dropFoot drop is the dropping of the forefoot due to weakness, damage to the peroneal nerve or paralysis of the muscles in the anterior portion of the lower leg. It is usually a symptom of a greater problem, not a disease in itself. It is characterized by the inability or difficulty in moving the ankle...
Treatment and research
- No Food and Drug AdministrationFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved therapies exist specifically for FSHD. - Occupational therapy can sometimes be used to help cope with new devices to make things easier.
Compounds of interest
ACVR2BACVR2B
Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor.-Interactions:ACVR2B has been shown to interact with SYNJ2BP and ACVR1B.-Further reading:...
is a compound identified in 2005/2006 by Johns Hopkinshttp://www.mdausa.org/research/060106myostatin_blocker.html. It increased muscle mass in a non-Muscular Dystrophy Mouse by up to 60% in two weeks.
MY0-029
MYO-029 is an experimental myostatinMyostatin
Myostatin is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor...
inhibiting drug developed by Wyeth Pharmaceuticals
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
for the treatment of muscular dystrophy. Myostatin is a protein that inhibits the growth of muscle tissue, MYO-029 is a recombinant human antibody designed to bind and inhibit the activity of myostatin. A 2005/2006 study was completed by Wyeth in Collegeville, PA and included participants afflicted with FSHD. The study could not prove its efficacy.
Procedures used to improve quality of life
- Scapular fusion: surgical fusion of the scapula to the thorax.
- Scapular bracing: a scapular brace helps stabilize the shoulder and correct glenohumeral positioning.
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.External links
- list of clinical trials for FSHD, Clinicaltrials.govClinicalTrials.govClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine at the National Institutes of Health, and is the largest clinical trials database, currently holding registrations from over 93,000 trials from more than 170 countries in the...
. - FSHD Global Research Foundation
- Photo and additional links at Washington University
- Richard Fields Center for FSHD and Neuromuscular Research
- National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, University of Rochester Medical Center
- The FSH Society was organized in 1991 and addresses issues and needs related to FacioScapuloHumeral muscular Dystrophy (FSHD).
- Pacific Northwest Friends of FSH Research
- European FSH patients Group & FSH-EUROPE
- The MDA addresses the gamut of issues related to Muscular Dystrophy.
- Muscular Dystrophy Association's website in Greece