Specialty neurology ICD-9-CM 359.1 DiseasesDB 7247 | ICD-10 G71.0 OMIM 158900 158901 MedlinePlus 000707 | |
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Facioscapulohumeral muscular dystrophy (FSHMD, FSHD or FSH)—originally named 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). FSHD is the third most common genetic disease of skeletal muscle. Orpha.net lists the prevalence as 4/100,000 while a 2014 population-based study in the Netherlands reported a significantly higher prevalence of 12 in 100,000.
Contents
- Symptoms
- FSHD Type 1 also called FSHMD1A 4q35 deletion
- FSHD Type 2
- A Unifying Theory
- FSH Society
- FSHD Foundation
- FSHD EUROPE
- Pathophysiology
- Testing
- Therapies
- Procedures used to improve quality of life
- History
- In Fiction
- References
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 can be threatened by respiratory insufficiency and up to 20% of affected individuals become severely disabled requiring use of a wheel chair or mobility scooter. In a Dutch study approximately 1% of patients required (nocturnal or diurnal) ventilatory support. Non-muscular symptoms frequently associated with FSHD include subclinical sensorineural hearing loss and retinal telangiectasia. In more than 95% of known cases, the disease is associated with contraction of the D4Z4 repeat in the 4q35 subtelomeric region of Chromosome 4. Seminal research published in August 2010 now shows the disease requires a second mechanism, which for the first time provides a unifying theory for its underlying genetics. The second mechanism is a "toxic gain of function" of the DUX4 gene, which is the first time in genetic research that a "dead gene" has been found to "wake up" and cause disease.
Building on the 2010 unified theory of FSHD, researchers in 2014 published the first proposed pathophysiology definition of the disease and four viable therapeutic targets for possible intervention points.
Symptoms
Because of the extreme variability of the disease, an authoritative and scientifically confirmed set of symptoms does not yet exist. The prevalence is widely placed at 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 Médicale (INSERM), listed the prevalence of 7/100,000 but the May 2014 version of this report places the prevalence at 4/100,000. A 2014 population-based study in the Netherlands reported a significantly higher prevalence of 12 in 100,000.[4]
Symptoms:
FSHD Type 1 (also called 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 4 of the human genome, of which a normal chromosome includes 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 from de novo (new) mutations. 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.
FSHD Type 2
A large family was reported with a phenotype indistinguishable from FSHD in which no pathological changes at the 4q site or translocation of 4q-10q are found. It had been suggested that this may be due to limitations in the available tests.
In 2012, a majority of FSHD2 cases were reported linked to mutations in the SMCHD1 gene on chromosome 18. This leads to substantially reduced levels of SMCHD1 protein, and subsequently, hypomethylation of the 4q D4Z4 region. The FSHD2 phenotype arises in individuals who inherited both the SMCHD1 mutations plus a normal sized D4Z4 region on a permissive 4qA allele. This establishes a genetic/mechanistic intersection of FSHD1 and FSHD2.
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 DUX4 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:
“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 (RNA) cause 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) because the DNA at the tip of chromosome 4 is less tightly coiled as a result of the deletions.
FSH Society
In 1991 the FSH Society was founded by two individuals with FSHD, Daniel Perez and Stephen Jacobsen. The FSH 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 FSH 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.
Pathophysiology
In 2014, researchers undertook a "review [of] how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease" and articulated how the unifying genetic model and subsequent research represent a "pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology." They proposed a consensus mechanism of pathophysiology for FSHD as a "inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle."
In more lay terms, the D4Z4 repeats (most people have about 200 or so) normally keep DUX4 repressed (the repeat-mediated repression). When there are drastically fewer repeats (approximately 10 or less) in addition to the small genetic change on Chromosome 4 called a haplotype polymorphism, DUX4 expresses itself (the inefficient repression component) via a complex set of mechanisms that make the genetic neighborhood around the DUX4 gene more conducive to gene expression (the epigenetic component). The figure on the right describes this process in detail.
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:
Therapies
- enhance the epigenetic repression of the D4Z4
- target the DUX4 mRNA, including altering splicing or polyadenylation;
- block the activity of the DUX4 protein
- inhibit the DUX4-induced process, or processes, that leads to pathology.
Procedures used to improve quality of life
History
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.
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.
A chronology of important milestones in the history of genetic research related to FSHD is included below in the Genetics section.
Over the years, FSHD has, at various times, been referred to as: