Research Updates
New Genes Explored in CMT and Dejerine-Sottas
MDA grantee Phillip Chance in the Departments of Pediatrics and Neurology at the
University of Washington in Seattle was on a research team that's closing in on
a gene that, when flawed, can produce Charcot-Marie-Tooth disease (CMT).The
precise gene hasn't yet been firmly identified, but two candidates have been
mapped to chromosome 16.
These genes, and the proteins for which they carry instructions, are thought to
influence myelin, a substance that coats nerve fibers and speeds transmission
of nerve signals. The team published its study in the January issue of the
American Journal of Human Genetics.
CMT is a common disorder of the peripheral nerves, bundles of nerve fibers
(axons) that run between the spinal cord and muscles and transmit signals for
movement and sensation.
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| Phillip Chance |
So far, nine genes have been identified that, when altered, produce the disorder
and/or a similar peripheral nerve condition, Dejerine-Sottas disease (DS).
(For a review of CMT and DS research, see "From Clear-Cut Endings to Complex Beginnings," Quest, vol. 8, no. 1.)
Several additional genes are suspected to cause these disorders because dozens
of proteins are likely involved in the structure and function of the peripheral
nerves.
The new finding involved studies of large families affected by CMT on which data
were collected in the 1970s.
"We're very excited about it," Chance said of his group's recent finding. "Since
1980, my colleagues and I have recognized that there had to be forms of CMT
type 1 [one of four major types] in addition to those known to be on chromosome
1, 17 and the X chromosome. We're looking for a specific gene now."
Two other research teams have found a gene on chromosome 8 that, when flawed,
can lead to CMT type 4A. A gene known as GDAP1, which researchers suspect may
have a role in helping nerve fibers and the cells that make myelin communicate
with each other, can lead to two manifestations of CMT4A. One type primarily
affects myelin, while the other primarily affects the nerve axons.
These studies, conducted by researchers in the United States, Tunisia, Spain and
France, are in the January issue of Nature Genetics. Jeffery Vance and Margaret
Pericak-Vance, former MDA grantees at Duke University in Durham, N.C., and
Faycal Hentati, an MDA grantee studying neuromuscular genetics at the National
Institute of Neurology in Tunis, Tunisia, were part of this research.
 |
| In Charcot-Marie-Tooth and Dejerine-Sottas diseases, nerve impulses are
slowed by a problem in the nerve fibers (axons) themselves, in the myelin
sheaths that surround each fiber, or in the way fibers and myelin-making cells
communicate with each other. |
These discoveries should soon improve CMT genetic diagnosis.
In another avenue of CMT and DS research, two recent studies have identified the
Wld(S) gene as potentially useful in helping peripheral nerves to survive under
a variety of adverse conditions.
The protein produced by the Wld(S) gene appears to protect peripheral nerves
from degeneration after injury or after exposure to neurotoxic drugs.
The studies were published in the December issues of Annals of Neurology and
Nature Neuroscience.
'Anti-Macrophage' Drugs Could Work for DMD
A new MDA-funded study suggests that drugs aimed at inflammatory cells called
macrophages could be more effective than the anti-inflammatory drugs currently
used for treating Duchenne muscular dystrophy (DMD).
DMD is caused by a genetic deficiency of dystrophin, a protein that sits just
inside the muscle cell membrane (surface). The loss of dystrophin leads to
breaks in the membrane, and destabilizes neuronal nitric oxide synthase (nNOS),
a protein which normally sends out tiny bursts of the gas nitric oxide (NO).
Muscles affected by DMD show signs of inflammation, including an abundance of
macrophages, and it's probably no coincidence that the anti-inflammatory drug
prednisone can slow the course of the disease. Still, it hasn't been clear how
macrophages fit into the disease process.
Since NO inhibits macrophages, James Tidball and his colleagues at the
University of California in Los Angeles speculated that the loss of NO might
leave muscles vulnerable to a macrophage invasion, and that restoring NO might
ameliorate DMD.
They tested their idea by giving mice with DMD extra copies of the nNOS gene.
That genetic boost not only restored the missing nNOS protein, but reduced
inflammation and other signs of DMD. In another experiment, Tidball and his
group showed that injecting the DMD mice with antibodies that stick to
macrophages had a similar effect.
The results, published in the Oct. 1 issue of the Journal of Cell Biology,
suggest that drugs designed to increase NO production or decrease macrophage
activity could be superior to prednisone for treating DMD, Tidball said.
He added that drugs that elevate NO might not be safe for people with DMD.
"There are also anti-inflammatories that are relatively specific for
macrophages which we are now looking into," he said.
New Heart Failure Device Gets Good Reviews
A mechanical device to assist a failing heart has received good first reviews
from a study published in the Nov. 15 issue of the New England Journal of
Medicine. The device could soon be useful for some people with neuromuscular
disorders affecting the heart.
The HeartMate VE, made by the Thoratec Corp. of Pleasanton, Calif., is an
implanted pump that substitutes for the heart's left ventricle, which normally
pumps blood to most of the body's organs. (The right ventricle pumps returning
blood through the lungs.) The device itself is worn internally, but lines
connecting it to a power source protrude through the skin.
The HeartMate and other such devices are designed to treat severe congestive
heart failure, which results from an inability of the heart muscle to pump
enough blood for the body's needs (see "The Heart is a Muscle, Too," Quest, vol. 6, no. 2). This type of
problem occurs often in Duchenne and Becker muscular dystrophies and
can also affect those with Friedreich's ataxia and some metabolic and mitochondrial muscle disorders.
 |
| The HeartMate, an implanted pump, can help compensate for a failing left
ventricle. Photo courtesy of Thoratec Corp. |
The new study, under the auspices of Columbia University in New York, the
National Institutes of Health and Thoratec, evaluated 129 people with end-stage
heart failure (defined as having symptoms even at rest) who weren't eligible
for cardiac transplantation. Survival rates more than doubled after a year.
The study authors concluded that "the use of a left ventricular assist device in
patients with advanced heart failure resulted in a clinically meaningful
survival benefit and an improved quality of life."
So far, the HeartMate is approved by the U.S. Food and Drug Administration only
as a bridge to cardiac transplantation, but Thoratec has submitted an
application to the FDA to make the device available to people with heart
failure who aren't eligible for transplantation, a group that would
likely include many people with neuromuscular diseases. The FDA has given an
"expedited review" status to the application, and the company hopes to secure
such approval in mid-2002.
Hispanic Families With OPMD Identified in New Mexico
MDA grantees David Bear in the Department of Cell Biology and Physiology at the
University of New Mexico Health Sciences Center in Albuquerque and Mark Becher
in the university's Department of Pathology were part of a multidisciplinary
team that recently identified 216 cases of oculopharyngeal muscular dystrophy
(OPMD) among Hispanic families in New Mexico.
OPMD primarily weakens the muscles of the upper eyelids and throat but can also
affect other muscles. Previously, most cases of OPMD had been thought to exist
in French Canada and Israel.
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| David Bear |
The case identification study, published in the Nov. 21 issue of the Journal of
the American Medical Association, was designed to help families and health
professionals understand and treat the symptoms of OPMD in New Mexico. Both
Bear and Becher have ongoing MDA funding to study the basic biology of OPMD.
"The thing that's amazing for me is that [OPMD] is a problem that goes all the
way from fundamental molecular biology to cell biology to tissue and organ
biology and now extends into population biology and population health," Bear
says. "It's a really interesting and important paradigm for how basic science
can be important for disease diagnosis, treatment and prevention, and MDA is
leading the way in supporting this kind of research."
Scientists Explore What Makes Eye Muscles Different
The six muscles that move the eyeball in all directions — the extraocular
muscles — have long been a subject for speculation. What's puzzling about these
muscles is that they're conspicuously spared in some neuromuscular diseases,
while in other neuromuscular conditions, they're specifically targeted by the
disease process.
MDA grantees Francisco Andrade in the Department of Neurology and John Porter in
the Department of Ophthalmology at Case Western Reserve University in Cleveland
were part of a research team that set about finding the differences between the
extraocular muscles and the rest of the body's voluntary muscles.
Among the differences these researchers listed in their paper, published in the
Oct. 9 issue of Proceedings of the National Academy of Sciences, are that eye
muscles have more nerve fibers
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| Six extraocular muscles — four straight and two diagonal — surround each
eyeball and allow it to move in all directions. |
attached per muscle fiber than do other muscles; that different genes for
muscle proteins are turned on in these muscles compared with other muscles; and
that the extraocular muscles produce a different array of immune system
components than other muscles.
The researchers conclude that these differences could explain why eye muscles
are spared in most muscular dystrophies and targeted in some disorders
involving the immune system, such as myasthenia gravis and some forms of hyperthyroid
myopathy.
Extra nerve fibers could help explain why these muscles are rarely affected in
disorders of the muscle-controlling nerve cells, such as amyotrophic lateral
sclerosis and spinal muscular atrophy.
Anesthesia Caution Urged for Children With Mitochondrial Myopathies
MDA grantee Margaret Sedensky of the Department of Anesthesiology at University
Hospitals of Cleveland was among those who recently found that some children
with mitochondrial myopathies are extremely sensitive to gas anesthesia.
Unfortunately, the study shows, individual reactions and risks can be hard to
predict.
Preliminary results of studies performed at Sedensky's institution have shown
that at least some children with these disorders become deeply unconscious more
quickly than do other children when exposed to the anesthetic sevoflurane. This
was the case for four of 16 children they studied, all of whom received
sevoflurane, most of them while undergoing muscle biopsies.
Sedensky said the findings should caution clinicians "to proceed very slowly
with very low doses of gaseous anesthetic for children with mitochondrial
diseases. Whether this same caution is necessary for other sorts of anesthetic
drugs isn't clear, but I think the prudent practitioner will view all the drugs
in his armamentarium a little more cautiously for these children."
Results of a completed study are scheduled to appear in the journal
Anesthesiology later this year.
Chemical Changes in Pregnancy Tied to Autoimmune Disorders
It's long been observed that disorders in which the immune system attacks the
body's own tissues (autoimmune disorders) worsen or sometimes occur for the
first time following pregnancy.
Polymyositis, dermatomyositis, myasthenia gravis, Lambert-Eaton syndrome and
some forms of hypo- and hyperthyroid myopathy are autoimmune, and
abnormal immunologic reactions may play a role in inclusion-body myositis and amyotrophic lateral sclerosis.
Now, researchers Ilia J. Elenkov at the National Institutes of Health in
Bethesda, Md., and colleagues have discovered some clues as to why this occurs.
Writing in the October issue of the Journal of Clinical Endocrinology and
Metabolism, the researchers report that levels of two substances associated
with immune system activity — TNF-alpha and interleukin-12 — fall sharply
during the third trimester of pregnancy and then rebound to normal levels after
childbirth. It's this rebound that may give rise to the problem, they suggest.
The low pregnancy levels of the two chemicals parallel high levels of cortisol,
norepinephrine and vitamin D3 that exist during pregnancy. Those three
substances have been shown to suppress interleukin-12 and TNF-alpha production
in lab experiments.
The researchers speculate that, after childbirth, when pregnancy hormones return
to normal or low-normal levels, the "brake" they put on the immune system is
removed, leading to a rebound of interleukin-12 and TNF-alpha and a shift
toward more cells that make these kinds of chemicals.
Enzyme Evidence Points to Amyloid Beta in IBM
Valerie Askanas and King Engel, MDA grantees at the University of Southern
California in Los Angeles, have long suspected that the muscle problems in inclusion-body
myositis (IBM) are related to a buildup of a toxic chemical known as
amyloid beta. Amyloid beta results from the splitting of a larger protein,
amyloid beta precursor protein, an act performed with the help of specific
enzymes.
Askanas, Engel and colleagues have published a report in the Dec. 8 issue of The
Lancet showing that two enzymes involved in splitting the larger protein are
elevated in IBM-affected muscle cells, lending significant weight to the
amyloid beta connection in this disease.
The researchers see targeting these enzymes as a potential treatment for IBM.
Interferon Trial Testing Higher Dose in Inclusion-Body Myositis
The drug interferon beta-1a, marketed as a treatment for multiple sclerosis
under the brand name Avonex, is undergoing further testing for possible benefit
in inclusion-body myositis (IBM), a muscle disorder that has proved
stubbornly resistant to therapy.
A pilot study of the drug in 30 people with IBM was recently conducted, with MDA
support, at six centers. Results, reported in the Nov. 13 issue of the journal
Neurology, showed the drug was safe and well tolerated but not effective.
(For more on IBM, see "Advances in Inclusion-Body Myositis" in Quest, vol. 8, no. 2.)
The new study, currently under way at five U.S. centers, as well as in Great
Britain and Canada, doubles the dose. The six-month study is expected to end in
September.
The interferon trial in IBM is being conducted at the University of Kansas
Medical Center, Kansas City; Brigham and Women's Hospital, Boston; University
of Rochester (N.Y.) Medical Center; Ohio State University Hospital, Columbus;
and University Texas Health Sciences Center, San Antonio.
Studies Yield New Insights on Myotubular Myopathy
A new study emphasizes the benefits of genetic testing for X-linked myotubular
myopathy (X-MTM), a disease that causes muscle weakness from birth.
In an MDA-funded study, Gail Herman and her colleagues at Ohio State University
in Columbus tested 62 boys with X-MTM for mutations in MTM1, the X chromosome
gene that's usually at the root of the disease. For the 50 boys who had a
detectable MTM1 mutation, the researchers evaluated the severity of symptoms
and the presence of the mutations in the boys' mothers.
In the February issue of Human Mutation, the group reported that certain
mutations were repeatedly associated with a mild course of the disease. Also,
of boys who had no family history of X-MTM, 88 percent of the mothers were
asymptomatic carriers of MTM1 mutations.
Finding mutations that lead to relatively mild X-MTM is "encouraging," Herman
said.
Unfortunately, the high carrier frequency among the boys' mothers "means that
even if there is no family history, most of the time the mother will be a
carrier and there would be a risk for another affected male [child]," she said.
Another study, led by French researcher Phillipe Poindron, raises the
possibility that the protein encoded by MTM1 — myotubularin — is required in
muscle-controlling nerve cells (motor neurons) rather than in muscle itself, as
most researchers believe.
In experiments described in the November issue of Neuromuscular Disorders, the
group removed immature muscle cells from people with X-MTM and placed them in a
dish with motor neurons from rats. The muscle cells formed connections with the
motor neurons, and appeared to develop the properties of normal muscle fibers —
not the signs of delayed maturity usually shown by X-MTM muscle cells.
Based on those results, Poindron and his team suggest that myotubularin activity
in motor neurons might direct proper muscle development.
(For more about this disorder, see "Myotubular Myopathy: A Dark Past Gives Way to a Bright Future," Quest, vol. 7,
no. 6.)
FSHD Research Funding Gets a Federal Boost
As a result of a meeting co-sponsored by MDA, government officials have
announced they're providing a million-dollar boost to research on facioscapulohumeral
muscular dystrophy (FSHD).
The May 2000 Conference on the Cause and Treatment of FSH Dystrophy brought
together scientists and officials from the National Institutes of Health to
encourage more federal funding for research on the disease.
The NIH in December announced it has awarded grants totaling $1.1 million to six
laboratories in the United States and the Netherlands to conduct basic and
clinical research on FSHD. 
MORE MDA RESEARCH NEWS
For up-to-the-minute news on MDA research developments, visit MDA's Web site at http://www.mda.org. Click on "Research" for information on recent
research developments and active clinical trials, and links to major
medical/research sites. Look at the Web site's "What's New" section for news
bulletins about breaking research announcements.
For research news about amyotrophic lateral sclerosis, see The ALS Newsletter or
go to http://www.als-mda.org. |
