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Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy

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Facioscapulohumeral muscular dystrophy
File:Timelapse Expression of DUX4 Protein in FSHD Cells.ogv Play media
Timelapse of DUX4 being expressed in FSHD Muscle Cells [1]
Specialty Neurology   Edit this on Wikidata 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/7/73/Blue_pencil.svg/20px-Blue_pencil.svg.png 2x” data-file-width=”600″ data-file-height=”600″ />

Facioscapulohumeral muscular dystrophy (FSHMD, FSHD or FSH)—originally named Landouzy-Dejerine [2] —is a usually autosomal dominant inherited form of muscular dystrophy (MD) [3] 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 [4] while a 2014 population-based study in the Netherlands reported a significantly higher prevalence of 12 in 100,000. [5]

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. [6] 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. [7] [8]

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. [9]

Contents

  • 1 Symptoms
  • 2 Genetics
    • 2.1 FSHD Type 1 (also called FSHMD1A) (4q35 deletion)
    • 2.2 FSHD Type 2
    • 2.3 A Unifying Theory
    • 2.4 Chronology of Important FSHD-related Genetic Research
    • 2.5 FSH Society
    • 2.6 FSHD Foundation
    • 2.7 FSHD-EUROPE
  • 3 Pathophysiology
  • 4 Testing
  • 5 Therapies
    • 5.1 Procedures used to improve quality of life
  • 6 History
  • 7 References
  • 8 External links

Symptoms[ edit ]

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 a prevalence of 7/100,000, but the May 2014 version of this report places the prevalence at 4/100,000. [4] A 2014 population-based study in the Netherlands reported a significantly higher prevalence of 12 in 100,000.[4]

FSHD can affect many skeletal muscles, with great variation among individuals. Muscle weakness usually becomes noticeable on one side of the body and not the other; this is a hallmark of the disease. Individual muscles can weaken while nearby muscles remain healthy.

Typical Symptoms, seen in many but not all patients:

  • 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 girdle weakness (difficulty working with the arms raised, sloping shoulder)
  • Asymmetrical weakening of the biceps
  • Asymmetrical weakening of tibialis anterior (shin muscle), causing foot drop
  • Asymmetrical loss of pectoral muscle
  • Loss of strength in abdominal muscles (causing a protuberant abdomen and lumbar lordosis)
  • Weakened diaphragm leading to respiratory insufficiency (seen more in older, more impaired patients)
  • Bilateral sensorineural hearing loss (present in 50 percent but clinically noticeable in fewer)
  • Coat’s disease-like retinal changes (retinal telangiectasia, macular oedema; mostly mild and not clinically significant) [10]

Genetics[ edit ]

Chromosome 4.svg

An illustration by Peter Jones PhD describing the complex interplay of genetics and epigenetics in FSHD.

FSHD Type 1 (also called FSHMD1A) (4q35 deletion)[ edit ]

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. [11] There are both heterochromatin and euchromatin structures within D4Z4 and one putative gene called DUX4 . [11] [12] 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. [11] 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. [13] Disease occurs when the translocation results in a critical loss of tandem repeats to the 4q site.

FSHD Type 2[ edit ]

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. [14] [15] It had been suggested that this may be due to limitations in the available tests. [16]

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. [17]

A Unifying Theory[ edit ]

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”. [8] 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 [7] 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: [7]

“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.

Chronology of Important FSHD-related Genetic Research[ edit ]

1884

  • Landouzy and Dejerine describe a form of childhood progressive muscle atrophy with a characteristic involvement of facial muscles and distinct from pseudohypertrophic (Duchenne’s MD) and spinal muscle atrophy in adults. [18]

1886

  • Landouzy and Dejerine describe progressive muscular atrophy of the scapulo-humeral type. [19]

1950

  • Tyler and Stephens study 1249 individuals from a single kindred with FSHD traced to a single ancestor and describe a typical Mendelian inheritance pattern with complete penetrance and highly variable expression. The term facioscapulohumeral dystrophy is introduced. [20]

1982

  • Padberg provides the first linkage studies to determine the genetic locus for FSHD in his seminal thesis “Facioscapulohumeral disease.” [21]

1987

  • The complete sequence of the Dystrophin gene ( Duchenne’s MD ) is determined. [22]

1991

  • The genetic defect in FSHD is linked to a region (4q35) near the tip of the long arm of chromosome 4 . [23]

1992

  • FSHD, in both familial and de novo cases , is found to be linked to a recombination event that reduces the size of 4q Eco R1 fragment to < 28 kb (50–300 kb normally). [24]

1993

  • 4q EcoR1 fragments are found to contain tandem arrangement of multiple 3.3-kb units (D4Z4), and FSHD is associated with the presence of < 11 D4Z4 units. [25]
  • A study of seven families with FSHD reveals evidence of genetic heterogeneity in FSHD. [26]

1994

  • The heterochromatic structure of 4q35 is recognized as a factor that may affect the expression of FSHD, possibly via position-effect variegation . [27]
  • DNA sequencing within D4Z4 units shows they contain an open reading frame corresponding to two homeobox domains, but investigators conclude that D4Z4 is unlikely to code for a functional transcript. [27] [28]

1995

  • The terms FSHD1A and FSHD1B are introduced to describe 4q-linked and non-4q-linked forms of the disease. [29]

1996

  • FSHD Region Gene1 ( FRG1 ) is discovered 100 kb proximal to D4Z4. [30]

1998

  • Monozygotic twins are identified with identical 23 kb EcoR1 fragments but vastly different clinical expression of FSHD. [31]

1999

  • Complete sequencing of 4q35 D4Z4 units reveals a promoter region located 149 bp 5′ from the open reading frame for the two homeobox domains, indicating a gene that encodes a protein of 391 amino acid protein (later corrected to 424 aa [32] ), given the name DUX4 . [33]

2001

  • Investigators assessed the methylation state ( heterochromatin is more highly methylated than euchromatin ) of DNA in 4q35 D4Z4. An examination of SmaI, MluI, SacII, and EagI restriction fragments from multiple cell types, including skeletal muscle, revealed no evidence for hypomethylation in cells from FSHD1 patients relative to D4Z4 from unaffected control cells or relative to homologous D4Z4 sites on chromosome 10 . However, in all instances, D4Z4 from sperm was hypomethylated relative to D4Z4 from somatic tissues. [34]

2002

  • A polymorphic segment of 10 kb directly distal to D4Z4 is found to exist in two allelic forms, designated 4qA and 4qB. FSHD1 is associated solely with the 4qA allele. [35]
  • Three genes (FRG1, FRG2 , ANT1 ) located in the region just centromeric to D4Z4 on chromosome 4 are found in isolated muscle cells from individuals with FSHD at levels 10 to 60 times greater than normal, showing a linkage between D4Z4 contractions and altered expression of 4q35 genes. [36]

2003

  • A further examination of DNA methylation in different 4q35 D4Z4 restriction fragments (BsaAI and FseI) showed significant hypomethylation at both sites for individuals with FSHD1, non-FSHD-expressing gene carriers, and individuals with phenotypic FSHD relative to unaffected controls. [37]

2004

  • Contraction of the D4Z4 region on the 4qB allele to < 38 kb does not cause FSHD. [38]

2006

  • Transgenic mice overexpressing FRG1 are shown to develop severe myopathy. [39]

2007

  • The DUX4 open reading frame is found to have been conserved in the genome of primates for over 100 million years, supporting the likelihood that it encodes a required protein. [40]
  • Researchers identify DUX4 mRNA in primary FSHD myoblasts and identify in D4Z4-transfected cells a DUX4 protein, the overexpression of which induces cell death. [32]
  • DUX4 mRNA and protein expression are reported to increase in myoblasts from FSHD patients, compared to unaffected controls. Stable DUX4 mRNA is transcribed only from the most distal D4Z4 unit, which uses an intron and a polyadenylation signal provided by the flanking pLAM region. DUX4 protein is identified as a transcription factor, and evidence suggests overexpression of DUX4 is linked to an increase in the target paired-like homeodomain transcription factor 1 ( PITX1 ). [41]

2009

  • The terms FSHD1 and FSHD2 are introduced to describe D4Z4-deletion-linked and non-D4Z4-deletion-linked genetic forms, respectively. In FSHD1, hypomethylation is restricted to the short 4q allele, whereas FSHD2 is characterized by hypomethylation of both 4q and both 10q alleles. [42]
  • Splicing and cleavage of the terminal (most telomeric ) 4q D4Z4 DUX4 transcript in primary myoblasts and fibroblasts from FSHD patients is found to result in the generation of multiple RNAs, including small noncoding RNA s, antisense RNA s and capped mRNAs as new candidates for the pathophysiology of FSHD. [43]

2010

  • A unifying genetic model of FSHD describes the requirement for FSHD-type deletions of D4Z4 to occur on a permissive allele containing a poly-A adenylation signal (PAS) in the pLAM1 region adjacent to the final D4Z4 unit. The non-permissive 4qB allele lacks a PAS, does not generate a stable DUX4 transcript, and is not linked to FSHD. The corresponding D4Z4 region on chromosome 10 (10q26) lacks a PAS altogether, and deletions in this region are not involved in FSHD. [44]
  • DUX4 is found actively transcribed in skeletal muscle biopsies and primary myoblasts. FSHD-affected cells produce a full length transcript, DUX4-fl, whereas alternative splicing in unaffected individuals results in the production of a shorter, 3′-truncated transcript (DUX4-s). The low overall expression of both transcripts in muscle is attributed to relatively high expression in a small number of nuclei (~ 1 in 1000). Higher levels of DUX4 expression in human testis (~100 fold higher than skeletal muscle) suggest a developmental role for DUX4 in human development. Higher levels of DUX4-s (vs DUX4-fl) are shown to correlate with a greater degree of DUX-4 H3K9me3-methylation. [45]

2012

  • Some, but not all, instances of FSHD2 are 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. [17]
  • The prevalence of FSHD-like D4Z4 deletions on permissive alleles is significantly higher than the prevalence of FSHD in the general population, challenging the criteria for molecular diagnosis of FSHD. [46]
  • When expressed in primary myoblasts, DUX4-fl acted as a transcriptional activator, producing a > 3-fold change in the expression of 710 genes. [47] A subsequent study using a larger number of samples identified DUX4-fl expression in myogenic cells and muscle tissue from unaffected relatives of FSHD patients, per se, is not sufficient to cause pathology, and that additional modifiers are determinants of disease progression. [48]
  • A mechanism is proposed in which DBE-T (D4Z4 Regulatory Element transcript), a long non-coding RNA transcribed from a 4q35 region proximal to D4Z4, is expressed in FSHD, leading to the recruitment of the Trithorax group protein Ash1L, an increase in H3k36me2-methylation, and ultimately de-repression of 4q35 genes. [49]

2013

  • Mutations in SMCHD1 are shown to act as a disease modifier, increasing the severity of FSHD1 in individuals who also exhibit a contraction of D4Z4. [50]
  • Transgenic mice carrying D4Z4 arrays from an FSHD1 allele (with 2.5 D4Z4 units), although lacking an obvious FSHD-like skeletal muscle phenotype, are found to recapitulate important genetic expression patterns and epigenetic features of FSHD. [51]

2014

  • DUX4-fl and downstream target genes are expressed in skeletal muscle biopsies and biopsy-derived cells of fetuses with FSHD-like D4Z4 arrays, indicating that molecular markers of FSHD are already expressed during fetal development. [52]
  • In an open access article in Skeletal Muscle, researchers “review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease” and articulate 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 describe the 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.” [9]

FSH Society[ edit ]

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. [53]

FSHD Foundation[ edit ]

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. [54]

FSHD-EUROPE[ edit ]

In 2009 the FSHD-EUROPE was founded by European associations. [55]

Pathophysiology[ edit ]

A schematic of D4Z4 locus on chromosome 4: The D4Z4 locus is in the sub-telomeric region of 4q. The figure shows a three repeat D4Z4 array. CEN indicates the centromeric end and TEL indicates the telomeric end. The DUX4 gene is shown as a gray rectangle with exon 1 and exon 2 in each repeat and exon 3 in the pLAM region telomeric to the last partial repeat (numbered 1, 2, and 3). PAS indicates the polyadenylation site on the permissive 4qA allele that is not present on the non-permissive 4qB allele or on chromosome 10. The arrowed lines represent: Blue, DBE-T transcripts (2.4, 4.4, and 9.8 kb) found in FSHD cells and reported to de-repress DUX4 expression; Black and red, transcripts in the sense and antisense direction were detected in both FSHD and control cells and might originate from the mapped sense promoters (black) and anti-sense promoters (red) with dashed lines indicating areas that might be degraded or produce si-like small RNAs. NDE, non-deleted element identified as the transcription start site for the DBE-T transcripts. [9]

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.” [9]

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[ edit ]

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: [56]

  • Creatine kinase (CK) level: This test measures the Creatine kinase enzyme 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 velocity (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 biopsy : 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.

Therapies[ edit ]

  • No approved therapies exist specifically for FSHD.
  • Based on the consensus model of pathophysiology, researchers propose four approaches for therapeutic intervention: [9]
    1. enhance the epigenetic repression of the D4Z4
    2. target the DUX4 mRNA, including altering splicing or polyadenylation;
    3. block the activity of the DUX4 protein
    4. inhibit the DUX4-induced process, or processes, that leads to pathology.
  • Physiotherapy could improve patients’ functional status by providing therapeutic exercises.
  • Occupational therapy can sometimes be used for ADL training and to help cope with new devices to make things easier.
  • Several compounds aimed at increasing muscle mass have been pursued including:
    • ACVR2B is a compound identified in 2005/2006 by researchers at Johns Hopkins [57] . It increased muscle mass in a non-muscular dystrophy mouse by up to 60% in two weeks.
    • MYO-029 ( Stamulumab ) is an experimental myostatin -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. [58] A 2005/2006 study was completed by Wyeth in Collegeville, PA, and included participants afflicted with FSHD. The study could not prove its efficacy and did not proceed further.
  • aTyr Pharma First FSHD Patient Study of Resolaris — First Physiocrine-Based Therapeutic Administered to Patients. [59]
    • “The Phase 1b/2 study is a double-blind, placebo-controlled, multiple ascending dose trial in up to 44 FSHD patients at multiple sites in the European Union. The exploratory trial is designed to evaluate safety, tolerability, pharmacokinetics and the biological activity of Resolaris in adult patients with FSHD. Our Resolaris FSHD trial represents the first patient administration of a naturally occurring protein derived from a new class of physiological modulators, Physiocrines. We believe this trial will be an important step in our plan to develop new medicines that will have a meaningful impact for patients by activating physiological pathways important to skeletal muscle health. [60]

Procedures used to improve quality of life[ edit ]

  • Quality of life can be measured with specific questionnaires. [61]
  • Scapular fusion: surgical fusion of the scapula to the thorax.
  • Scapular bracing: a scapular brace helps stabilize the shoulder and correct glenohumeral positioning.

History[ edit ]

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. [62] 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. [11]

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. [9]

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:

  • Landouzy-Dejerine [2]
  • Landouzy-Dejerine syndrome [62]
  • Erb-Landouzy-Dejerine syndrome [62]
  • Landouzy-Dejerine dystrophy or atrophy [62]
  • faciohumeroscapular

References[ edit ]

  1. ^ Rickard, Amanda; Petek, Lisa; Miller, Daniel (August 5, 2015). “Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways” . Hum. Mol. Genet. 24: 5901–14. doi : 10.1093/hmg/ddv315 . PMC   4581613 . PMID   26246499 . Retrieved September 10, 2015.

  2. ^ a b disease overview , MDA , date accessed 6 March 2007
  3. ^ Lemmers RJ, Wohlgemuth M, van der Gaag KJ, et al. (November 2007). “Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy” . Am. J. Hum. Genet. 81 (5): 884–94. doi : 10.1086/521986 . PMC   2265642 . PMID   17924332 .
  4. ^ a b Prevalence of rare diseases: Bibliographic data , www.orpha.net, May 2014, Number 1, Orphanet Report Series
  5. ^ Deenen JC, Arnts H, van der Maarel SM, Padberg GW, Verschuuren JJ, Bakker E, Weinreich SS, Verbeek AL, van Engelen BG (2014). “Population-based incidence and prevalence of facioscapulohumeral dystrophy” . Neurology. 83 (12): 1056–9. doi : 10.1212/WNL.0000000000000797 . PMC   4166358 . PMID   25122204 .
  6. ^ Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW (2004). “Ventilatory support in facioscapulohumeral muscular dystrophy”. Neurology. 63 (1): 176–8. doi : 10.1212/01.wnl.0000133126.86377.e8 . PMID   15249635 .
  7. ^ a b c Kolata, Gina (19 August 2010). “Reanimated ‘Junk’ DNA Is Found to Cause Disease” . The New York Times . Retrieved 29 August 2010.
  8. ^ a b Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM (19 August 2010). “A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy” . Science. 329 (5999): 1650–3. doi : 10.1126/science.1189044 . PMC   4677822 . PMID   20724583 .
  9. ^ a b c d e f Tawil, Rabi; van der Maarel, SM; Tapscott, SJ (10 June 2014). “Facioscapulohumeral dystrophy: the path to consensus on pathophysiology” . Skeletal Muscle. 4 (1): 12. doi : 10.1186/2044-5040-4-12 .
  10. ^ Lindner, Moritz; Holz, Frank G; Charbel Issa, Peter (2016-04-27). “Spontaneous resolution of retinal vascular abnormalities and macular oedema in facioscapulohumeral muscular dystrophy” . Clinical & Experimental Ophthalmology. 44 (7): 627–628. doi : 10.1111/ceo.12735 . ISSN   1442-6404 .
  11. ^ a b c d Impossible Things: Through the looking glass with FSH Dystrophy Researchers , Margaret Wahl, MDA , Quest magazine, Vol 14, No 2, March–April 2007
  12. ^ Dixit M, Ansseau E, Tassin A, et al. (November 2007). “DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1” . Proc. Natl. Acad. Sci. U.S.A. 104 (46): 18157–62. doi : 10.1073/pnas.0708659104 . PMC   2084313 . PMID   17984056 .
  13. ^ Rossi M, Ricci E, Colantoni L, et al. (2007). “The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure” . BMC Med. Genet. 8: 8. doi : 10.1186/1471-2350-8-8 . PMC   1821008 . PMID   17335567 .
  14. ^ Gilbert JR, Stajich JM, Wall S, et al. (August 1993). “Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)” . Am. J. Hum. Genet. 53 (2): 401–8. PMC   1682358 . PMID   8328457 .
  15. ^ Speer MC, Pericak-Vance MA, Stajich JM, et al. (September 1997). “Further exclusion of FSHD1B from the telomeric region of 10q” . Neurogenetics. 1 (2): 151–2. doi : 10.1007/s100480050023 . PMID   10732819 . Archived from the original on 1999-11-22. Retrieved 2009-02-19.
  16. ^ Deak KL, Lemmers RJ, Stajich JM, et al. (February 2007). “Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4” . Neurology. 68 (8): 578–82. doi : 10.1212/01.wnl.0000254991.21818.f3 . PMID   17229919 .
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  44. ^ Lemmers, RJ; van der Vliet, PJ; Klooster, R; et al. (Sep 24, 2010). “A unifying genetic model for facioscapulohumeral muscular dystrophy” (PDF). Science. 329 (5999): 1650–1653. doi : 10.1126/science.1189044 . PMC   4677822 . PMID   20724583 . Archived from the original (PDF) on 2014-06-05.
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  62. ^ a b c d Landouzy-Dejerine syndrome , whonamedit.com, date accessed March 11, 2007

External links[ edit ]

Classification
D
  • ICD – 10 : G71.0
  • ICD – 9-CM : 359.1
  • OMIM : 158900 158901
  • MeSH : D020391
  • DiseasesDB : 7247
External resources
  • MedlinePlus : 000707
  • eMedicine : neuro/133
  • Patient UK :
    Facioscapulohumeral muscular dystrophy
  • GeneReviews : Facioscapulohumeral muscular dystrophy
  • Orphanet : 269
  • list of clinical trials for FSHD , Clinicaltrials.gov .
  • fsh at NIH / UW GeneTests
Wikimedia Commons has media related to FSHD .
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Muscular dystrophy
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  • dystrophin
    • Becker’s
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      Genetics Home Reference, Your Guide to Understanding Genetic Conditions

      1. Home
      2. Health Conditions
      3. Facioscapulohumeral muscular dystrophy

      Facioscapulohumeral muscular dystrophy

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      Description

      Facioscapulohumeral muscular dystrophy is a disorder characterized by muscle weakness and wasting (atrophy). This condition gets its name from the muscles that are affected most often: those of the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The signs and symptoms of facioscapulohumeral muscular dystrophy usually appear in adolescence. However, the onset and severity of the condition varies widely. Milder cases may not become noticeable until later in life, whereas rare severe cases become apparent in infancy or early childhood.

      Weakness involving the facial muscles or shoulders is usually the first symptom of this condition. Facial muscle weakness often makes it difficult to drink from a straw, whistle, or turn up the corners of the mouth when smiling. Weakness in muscles around the eyes can prevent the eyes from closing fully while a person is asleep, which can lead to dry eyes and other eye problems. For reasons that are unclear, weakness may be more severe in one side of the face than the other. Weak shoulder muscles tend to make the shoulder blades (scapulae) protrude from the back, a common sign known as scapular winging. Weakness in muscles of the shoulders and upper arms can make it difficult to raise the arms over the head or throw a ball.

      The muscle weakness associated with facioscapulohumeral muscular dystrophy worsens slowly over decades and may spread to other parts of the body. Weakness in muscles of the lower legs can lead to a condition called foot drop, which affects walking and increases the risk of falls. Muscular weakness in the hips and pelvis can make it difficult to climb stairs or walk long distances. Additionally, affected individuals may have an exaggerated curvature of the lower back ( lordosis ) due to weak abdominal muscles. About 20 percent of affected individuals eventually require the use of a wheelchair.

      Additional signs and symptoms of facioscapulohumeral muscular dystrophy can include mild high-tone hearing loss and abnormalities involving the light-sensitive tissue at the back of the eye ( the retina ). These signs are often not noticeable and may be discovered only during medical testing. Rarely, facioscapulohumeral muscular dystrophy affects the heart (cardiac) muscle or muscles needed for breathing.

      Researchers have described two types of facioscapulohumeral muscular dystrophy: type 1 (FSHD1) and type 2 (FSHD2). The two types have the same signs and symptoms and are distinguished by their genetic cause.

      Related Information

      • What does it mean if a disorder seems to run in my family?
      • What is the prognosis of a genetic condition?
      • Genetic and Rare Diseases Information Center

      Frequency

      Facioscapulohumeral muscular dystrophy has an estimated prevalence of 1 in 20,000 people. About 95 percent of all cases are FSHD1; the remaining 5 percent are FSHD2.

      Related Information

      • What information about a genetic condition can statistics provide?
      • Why are some genetic conditions more common in particular ethnic groups?

      Causes

      Facioscapulohumeral muscular dystrophy is caused by genetic changes involving the long (q) arm of chromosome 4 . Both types of the disease result from changes in a region of DNA near the end of the chromosome known as D4Z4. This region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs (3.3 kb) long. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups (consisting of one carbon atom and three hydrogen atoms) attached to the DNA. The addition of methyl groups turns off (silences) genes, so hypermethylated regions of DNA tend to have fewer genes that are turned on (active). Facioscapulohumeral muscular dystrophy results when the D4Z4 region is hypomethylated, with a shortage of attached methyl groups. In FSHD1, hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. In FSHD2, hypomethylation most often results from mutations in a gene called SMCHD1 , which provides instructions for making a protein that normally hypermethylates the D4Z4 region. However, about 20 percent of people with FSHD2 do not have an identified mutation in the SMCHD1 gene, and the cause of the hypomethylation is unknown.

      Hypermethylation of the D4Z4 region normally keeps a gene called DUX4 silenced in most adult cells and tissues. The DUX4 gene is located in the segment of the D4Z4 region closest to the end of chromosome 4. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is active, researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

      The DUX4 gene is located next to a regulatory region of DNA on chromosome 4 known as a pLAM sequence, which is necessary for the production of the DUX4 protein. Some copies of chromosome 4 have a functional pLAM sequence, while others do not. Copies of chromosome 4 with a functional pLAM sequence are described as 4qA or “permissive.” Those without a functional pLAM sequence are described as 4qB or “non-permissive.” Without a functional pLAM sequence, no DUX4 protein is made. Because there are two copies of chromosome 4 in each cell, individuals may have two “permissive” copies of chromosome 4, two “non-permissive” copies, or one of each. Facioscapulohumeral muscular dystrophy can only occur in people who have at least one “permissive” copy of chromosome 4. Whether an affected individual has a contracted D4Z4 region or a SMCHD1 gene mutation, the disease results only if a functional pLAM sequence is also present to allow DUX4 protein to be produced.

      Studies suggest that mutations in the SMCHD1 gene, which cause FSHD2, can also increase the severity of the disease in people with FSHD1. Researchers suspect that the combination of a contracted D4Z4 region and a SMCHD1 gene mutation causes the D4Z4 region to have even fewer methyl groups attached, which allows the DUX4 gene to be highly active. In people with both genetic changes, the overactive gene leads to severe muscle weakness and atrophy.

      Learn more about the genes and chromosome associated with facioscapulohumeral muscular dystrophy

      • DUX4
      • SMCHD1
      • chromosome 4

      Related Information

      • What is a gene?
      • How can gene mutations affect health and development?
      • Can changes in the structure of chromosomes affect health and development?
      • More about Mutations and Health

      Inheritance Pattern

      FSHD1 is inherited in an autosomal dominant pattern, which means one copy of the shortened D4Z4 region on a “permissive” chromosome 4 is sufficient to cause the disorder. In most cases, an affected person inherits the altered chromosome from one affected parent . Other people with FSHD1 have no history of the disorder in their family. These cases are described as sporadic and are caused by a new (de novo) D4Z4 contraction on one copy of a “permissive” chromosome 4.

      FSHD2 is inherited in a digenic pattern, which means that two independent genetic changes are necessary to cause the disorder. To have FSHD2, an individual must inherit a mutation in the SMCHD1 gene (which is located on chromosome 18 ) and, separately, they must inherit one copy of a “permissive” chromosome 4. Affected individuals typically inherit the SMCHD1 gene mutation from one parent and the “permissive” chromosome 4 from the other parent. (Because neither parent has both genetic changes in most cases, they are typically unaffected.)

      Related Information

      • What does it mean if a disorder seems to run in my family?
      • What are the different ways in which a genetic condition can be inherited?
      • Are chromosomal disorders inherited?
      • More about Inheriting Genetic Conditions

      Diagnosis & Management Links

      Genetic Testing Information (3 links)

      • What is genetic testing?
      • Genetic Testing Registry: Facioscapulohumeral muscular dystrophy
      • Genetic Testing Registry: Facioscapulohumeral muscular dystrophy 2

      Research Studies from ClinicalTrials.gov (1 link)

      • ClinicalTrials.gov

      Other Diagnosis and Management Resources (2 links)

      • GeneReview: Facioscapulohumeral Muscular Dystrophy
      • MedlinePlus Encyclopedia: Facioscapulohumeral Muscular Dystrophy

      Related Information

      • How we cover diagnosis and management of health conditions
      • How are genetic conditions diagnosed?
      • How are genetic conditions treated or managed?
      • How can I find a genetics professional in my area?

      Other Names for This Condition

      • facio-scapulo-humeral dystrophy
      • facioscapulohumeral atrophy
      • facioscapulohumeral type progressive muscular dystrophy
      • facioscapuloperoneal muscular dystrophy
      • FSH muscular dystrophy
      • FSHD
      • muscular dystrophy, facioscapulohumeral

      Related Information

      • How are genetic conditions and genes named?

      Additional Information & Resources

      Health Information from MedlinePlus (2 links)

      • Encyclopedia: Facioscapulohumeral Muscular Dystrophy
      • Health Topic: Muscular Dystrophy

      Genetic and Rare Diseases Information Center (1 link)

      • Facioscapulohumeral muscular dystrophy

      Additional NIH Resources (1 link)

      • National Institute for Neurological Disorders and Stroke: Muscular Dystrophy Information Page

      Educational Resources (3 links)

      • MalaCards: facioscapulohumeral muscular dystrophy 1
      • Orphanet: Facioscapulohumeral dystrophy
      • University of Washington: Facioscapulohumeral Muscular Dystrophy: Making an Informed Choice About Genetic Testing (PDF)

      Patient Support and Advocacy Resources (8 links)

      • Friends of FSH Research
      • FSH Society
      • Muscular Dystrophy Association
      • Muscular Dystrophy Canada
      • Muscular Dystrophy UK
      • National Organization for Rare Disorders (NORD)
      • National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members
      • Resource list from the University of Kansas Medical Center: Muscular dystrophy / atrophy

      Clinical Information from GeneReviews (1 link)

      • Facioscapulohumeral Muscular Dystrophy

      Scientific Articles on PubMed (1 link)

      • PubMed

      Catalog of Genes and Diseases from OMIM (2 links)

      • FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1
      • FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2

      Sources for This Page

      • Lemmers RJ, O’Shea S, Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul Disord. 2012 May;22(5):463-70. doi: 10.1016/j.nmd.2011.09.004. Epub 2011 Dec 16.
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      • Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454. Epub 2012 Nov 11.
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      • Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010 Sep 24;329(5999):1650-3. doi: 10.1126/science.1189044. Epub 2010 Aug 19.
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      • Lemmers RJLF, Miller DG, van der Maarel SM. Facioscapulohumeral Muscular Dystrophy. 1999 Mar 8 [updated 2014 Mar 20]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1443/
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      • Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen MP, Straasheijm KR, Debipersad RD, Vos-Versteeg M, Salviati L, Casarin A, Pegoraro E, Tawil R, Bakker E, Tapscott SJ, Desnuelle C, van der Maarel SM. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. 2013 Oct 3;93(4):744-51. doi: 10.1016/j.ajhg.2013.08.004. Epub 2013 Sep 26.
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      • Sacconi S, Salviati L, Desnuelle C. Facioscapulohumeral muscular dystrophy. Biochim Biophys Acta. 2015 Apr;1852(4):607-14. doi: 10.1016/j.bbadis.2014.05.021. Epub 2014 May 29. Review.
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      • Tawil R, van der Maarel SM, Tapscott SJ. Facioscapulohumeral dystrophy: the path to consensus on pathophysiology. Skelet Muscle. 2014 Jun 10;4:12. doi: 10.1186/2044-5040-4-12. eCollection 2014. Review.
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      • de Greef JC, Lemmers RJ, Camaño P, Day JW, Sacconi S, Dunand M, van Engelen BG, Kiuru-Enari S, Padberg GW, Rosa AL, Desnuelle C, Spuler S, Tarnopolsky M, Venance SL, Frants RR, van der Maarel SM, Tawil R. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010 Oct 26;75(17):1548-54. doi: 10.1212/WNL.0b013e3181f96175.
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      Reviewed : August 2014

      Published : November 27, 2018

      The resources on this site should not be used as a substitute for professional medical care or advice. Users with questions about a personal health condition should consult with a qualified healthcare professional .

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      Facioscapulohumeral Muscular Dystrophy (FSH, FSHD)

      Facioscapulohumeral Muscular Dystrophy (FSH, FSHD)

      What is facioscapulohumeral muscular dystrophy?

      Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder in which the muscles of the face, shoulder blades and upper arms are among the most affected.

      The long name comes from facies, the Latin word and medical term for face; scapula, the Latin word and anatomical term for shoulder blade; andhumerus, the Latin word for upper arm and the anatomical term for the bone that goes from the shoulder to the elbow.

      The term muscular dystrophy means progressive muscle degeneration, with increasing weakness and atrophy (loss of bulk) of muscles. In FSHD, weakness first and most seriously affects the face, shoulders and upper arms, but the disease usually also causes weakness in other muscles.

      What are the symptoms of FSHD?

      FSHD usually begins before age 20, with weakness and atrophy of the muscles around the eyes and mouth, shoulders, upper arms and lower legs. Later, weakness can spread to abdominal muscles and sometimes hip muscles.

      Some experts divide FSHD into adult-onset and infantile-onset forms. The adult-onset (which includes FSHD that begins in adolescence) is far more common.

      In either type of FSHD, facial weakness can start in childhood. Occasionally, other FSHD symptoms appear in early childhood. Infantile-onset FSHD generally runs a more pronounced course with regard to muscle weakness and sometimes also affects hearing and vision. Preliminary evidence suggests that the infantile-onset form is associated with a larger piece of missing DNA. For more, see  Signs and Symptoms .

      What causes FSHD?

      FSHD may be inherited through either the father or the mother, or it may occur without a family history. It is almost always associated with a genetic flaw (mutation) that leads to a shorter than usual segment of DNA on chromosome 4. The segment isn’t part of any particular gene, but it nevertheless seems to interfere with the correct processing of genetic material.

      A small number of people have a disorder that looks exactly like FSHD but don’t have the short segment on chromosome 4. The genetic cause of their disorder has yet to be identified.

      For more about the genetic causes of FSHD, see  Causes/Inheritance . For more about how the missing chromosome 4 segment may cause FSHD, see  Research .

      What is the progression of FSHD?

      FSHD usually progresses very slowly and rarely affects the heart or respiratory system. Most people with the disease have a normal life span.

      What is the status of research in FSHD?

      In 2009, MDA-supported researchers found that pieces of a gene called DUX4 are abnormally activated in FSHD-affected cells, leading to production of potentially toxic proteins. Blocking the erroneously activated genes or the proteins made from them seems a likely pathway for the eventual treatment of FSHD. For more, see  Research .

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      • About Facioscapulohumeral Muscular Dystrophy (FSH, FSHD)
      • Signs and Symptoms
      • Diagnosis
      • Causes/Inheritance
      • Medical Management
      • Research

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