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Facioscapulohumeral muscular dystrophy (FSHD)
is a slowly progressive disorder that typically begins between the ages of 6 and
20. It is estimated that 4-5 people per 100,000 population have FSHD. The first
symptom that patients most commonly report is weakness of certain skeletal (voluntary)
muscles; e.g., difficulty holding arms over the head for even a few minutes.
After many years of searching
by an international scientific consortium, the first FSHD gene was located on
the tip of human chromosome 4 in 1990. The tips of chromosomes, called telomeres,
are involved in chromosome protection and division and are very difficult regions
of DNA to study because they generally have few genes and are full of repetitive
pieces of DNA that look very much alike. In most cases the function of this repetitive
DNA is poorly understood. In 1992 the primary defect, the loss of certain types
of repetitive DNA, was discovered in FSHD patients. Briefly, it was found that
identical blocks of DNA each of approximately 3,300 base pairs (the measurement
of DNA that signifies the length of the sequence, or individual chemicals, which
make up the strand of DNA) were lined up like beads on a string close to one end
of chromosome 4. Unaffected individuals have anywhere from one dozen to several
dozen of these identical blocks. Patients with FSHD, however, have fewer blocks
and recent research seems to indicate that the fewer the blocks, the more severe
the FSHD will be. Although it is still not understood why these DNA blocks are
lost, it was assumed that they must either be part of a gene or lie very close
to the FSHD gene. Therefore, optimism was high that the affected gene would be
isolated very shortly.
To summarize a long story, after five years of
research no disease-causing gene has been found. In fact this region, although
it may still be hiding some secrets, seems to contain few genes at all. The repeat
blocks do not themselves seem to be part of a gene. How the loss of the DNA blocks
cause FSHD is unknown. In recent years, however, it has become increasingly clear
that there is no readily apparent FSHD gene in this area. The suspicion has been
growing that FSHD may be caused by a relatively rare complex genetic mechanism
known as "position effect variegation". Simply put in the case of FSHD,
this means that the loss of the DNA blocks alters the structure, the appearance,
or the interactions of the DNA in this region in such a way as to affect the function
of a gene or genes that lie on another part of chromosome 4 or even, although
it is less likely, on a different chromosome. If this theory is correct, it would
have the benefit of providing a genetic explanation for the disease, but would
magnify many fold the difficulties of isolating this gene since the obvious question
is, where exactly do you look for it? If the interaction is on chromosome 4, then
how far away is it and if on another chromosome, then which chromosome is it?
In other words, before we can find the needle we have to determine which haystack
to look in.
Scientists working on isolating the FSHD gene are now taking
three very broad approaches in trying to deal with these difficulties. First,
they are moving from the tip of chromosome 4 toward the center isolating and studying
DNA and genes as they go. This approach is extremely laborious and expensive,
but necessary. If the gene is relatively close to the block region, then the chromosome
4 FSHD gene will be isolated depending on just how close it is. Second, they are
looking at interactions of the altered blocks of DNA with other regions and chromosomes.
It is known that many other chromosomes have very similar types of DNA. In fact,
a major recent discovery is that the chromosome 4 blocks are exchanged, sometimes
unevenly, with similar blocks on chromosome 10. This has made diagnosis of the
FSHD more accurate, but does not at the moment look as if it will immediately
help in the isolation of the gene. Lastly, there may be individuals with FSHD
who have their FSHD gene(s) altered by processes other than the loss of DNA blocks,
or other forms of FSHD such as those being worked on here at Duke University Medical
Center that may yield valuable insight into how changes in genes cause FSHD and
the location of the chromosome 4 gene(s).
Unfortunately, in some ways
less is known about the location of the gene than was thought to be known in 1992,
but in the real sense far more is known today. Diagnoses are more accurate and
we believe that we understand more about the potential genetic mechanisms involved.
The FSHD gene(s) will be found, but how much longer the search will be is an open
question.
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For information on study participation, please contact:
Jeffrey M. Stajich, MA, PA-C
E-mail: staji001@chg.duhs.duke.edu
Prenatal, presymptomatic, and
diagnostic testing for FSHD is available for chromosome 4-linked families through:
Athena Diagnostics, Inc.
Reference Lab
Worcester, MA
Elizabeth
Couchon, MS, CGC
Phone: (508) 756-2886 ext3108
Fax: (508) 753-5601
E-mail: genetic.counselor@athenadiagnostics.com
University of Iowa Hospitals and Clinics
Department of Pathology
Iowa City, IA
Jeanine Beranek
Phone: (866) 844-2522
Fax: (319) 384-7213
E-mail: jeanine-beranek@uiowa.edu
Children's Hospital of Eastern Ontario
DNA Diagnostic Laboratory Ottawa
Ontario, Canada K1H 8L1
Director: Robert Korneluk, PhD
Main Contact: Gabrielle
Mettler, MS
Phone: (613) 738-3277
Fax: (613) 738-4822
E-mail: genetics@cheo.on.ca
Alberta Children's Hospital
Molecular Diagnostic Laboratory Calgary
Alberta, Canada T2T 5C7
Director: Peter Bridge, PhD
Main Contact: The
Laboratory
Phone: (403) 229-7026
Fax: (403) 229-7624
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As CHG researchers continue to define
the genetic causes of FSHD, they publish their findings in leading academic journals
and share their knowledge with colleagues at meetings and conferences.
FSHD
Research Publications
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FSHD Support Organizations
Muscular Dystrophy Association
3300 E. Sunrise Drive
Tucson, AZ 85718-3208
Phone: (800) 572-1717
Fax: (602) 529-5300
E-mail: mda@mdausa.org
FacioScapuloHumeral
Muscular Dystrophy Society (FSH Society)
To schedule an appointment at Duke University Medical Center for medical
care and/or genetic counseling for facioscapulohumeral muscular dystrophy, please
contact:
Muscular Dystrophy Association
3203 Womans Club Drive Suite
207,
Raleigh, NC 27612
Phone: (919) 783-0222
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