Facioscapulohumeral Muscular Dystrophy
Facioscapulohumeral Muscular Dystrophy
Facioscapulohumeral Muscular Dystrophy
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.
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
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to be highly active. In people with both genetic changes, the overactive gene leads to
severe muscle weakness and atrophy.
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.)
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Research Studies from ClinicalTrials.gov
• ClinicalTrials.gov
https://clinicaltrials.gov/ct2/results?cond=%22facioscapulohumeral+muscular
+dystrophy%22
Educational Resources
• MalaCards: facioscapulohumeral muscular dystrophy 1
https://www.malacards.org/card/facioscapulohumeral_muscular_dystrophy_1
• Orphanet: Facioscapulohumeral dystrophy
https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=269
• University of Washington: Facioscapulohumeral Muscular Dystrophy: Making an
Informed Choice About Genetic Testing
http://depts.washington.edu/neurolog/images/neurogenetics/fshd.pdf
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Patient Support and Advocacy Resources
• Friends of FSH Research
http://www.fshfriends.org/
• FSH Society
https://www.fshsociety.org/
• Muscular Dystrophy Association
https://www.mda.org/disease/facioscapulohumeral-muscular-dystrophy
• Muscular Dystrophy Canada
http://www.muscle.ca/about-muscular-dystrophy/types-of-neuromuscular-disorders/
facioscapulohumeral-dystrophy/
• Muscular Dystrophy UK
https://www.musculardystrophyuk.org/about-muscle-wasting-conditions/
facioscapulohumeral-muscular-dystrophy-fsh/
• National Organization for Rare Disorders (NORD)
https://rarediseases.org/rare-diseases/facioscapulohumeral-muscular-dystrophy/
• National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular
Dystrophy Patients and Family Members
https://www.urmc.rochester.edu/neurology/national-registry.aspx
• Resource list from the University of Kansas Medical Center: Muscular dystrophy /
atrophy
http://www.kumc.edu/gec/support/muscular.html
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Medical Genetics Database from MedGen
• Facioscapulohumeral muscular dystrophy
https://www.ncbi.nlm.nih.gov/medgen/320407
• Facioscapulohumeral muscular dystrophy 2
https://www.ncbi.nlm.nih.gov/medgen/320405
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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.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24940479
Free article on PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060068/
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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.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20975055
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