From Clear-Cut Endings to Complex Beginnings:
Researchers Probe the Origins of Charcot-Marie-Tooth Disease
CMT1A and HNPP: Flip Sides of the Same Coin
In the late 1980s, while the CMT gene hunt was gaining momentum,
neurologist Phillip Chance was searching for the genetic cause of an apparently
unrelated neuropathy — hereditary neuropathy with liability to pressure palsies
(HNPP). To his surprise, Chance's investigation revealed that HNPP and most
CMT1 cases result from the same mutation event. Once that mutation occurs, the
emergence of either HNPP or CMT1 in a family is sort of like flipping a coin.HNPP is an inherited disorder that causes temporary attacks of
paralysis typically localized to a single limb. Those attacks take weeks to
months to recover from, and are brought on by palsy — the malfunction of a
peripheral nerve that serves the affected limb. "[HNPP] is so different
clinically from CMT," says Chance, "that few people suspected it had anything
to do with CMT." But in 1992, Chance published an MDA-funded study showing that HNPP
is genetically related to the most common form of CMT1 — CMT1A. Earlier that
year, MDA-funded researchers had established that CMT1A is caused by a
duplication of the PMP22 gene on chromosome 17. (It's important to remember
that, except for the X and Y chromosomes, everyone normally has two copies of
each chromosome, one from dad's sperm and one from mom's egg. So, having the
duplication means that a person has three copies of the PMP22 gene.) The
resulting overproduction of the PMP22 protein — a component of myelin — is
somehow detrimental to Schwann cells.Though it's a rare event, the duplication usually arises while
single copies of dad's chromosomes are being parceled into his sperm. As his
two copies of chromosome 17 are preparing for separation into the sperm, a
piece of genetic material containing PMP22 is accidentally removed from one
copy of the chromosome and inserted into the other. So, one sperm receives an
extra PMP22 gene, and one sperm loses its PMP22 gene. "The existence of the duplication predicted that there would be a
reciprocal deletion, but it was generally assumed that the deletion would be
lethal, of no consequence, or it could have resulted in a disorder which wasn't
necessarily a peripheral neuropathy," says Chance, who's now at the University
of Washington in Seattle.Chance's research showed that deletion of the PMP22 gene — the flip
side of the mutation underlying CMT1A — is the cause of HNPP. "We had no reason
to think that studying HNPP would give us any particular insights into CMT,"
says Chance. But it has helped make clear that peripheral nerve is sensitive to
high or low levels of PMP22.
"The relationship with CMT has also done a lot to bring HNPP into
the clinical arena," says Chance. |
Protective Genes and Potential Treatments
So far, researchers haven't identified any specific chemical messages that
Schwann cells produce to maintain axon health. However, they're working on
other promising ways to prevent the axonal damage that underlies CMT.
With MDA support, Shy is developing a gene therapy method to supply ailing axons
with glial-derived neurotrophic factor (GDNF), a naturally occurring protein
that stimulates nerve cell growth and survival. Rather than preventing
demyelination, the goal of gene therapy with GDNF is to protect axons from the
effects of demyelination.
An advantage of Shy's approach is that it has potential for treating any type of
CMT, regardless of the underlying genetic defect.
In contrast, conventional gene therapy — trying to correct a genetic defect by
supplying normal copies of the defective gene — would have to be tailored to
each of the roughly 20 CMT genes.
Besides that, many cases of demyelinating CMT aren't caused by loss of an
essential gene, but by a toxic gain of gene function (see "CMT1A
and HNPP"). In those cases, conventional gene therapy won't work
because "giving more of the natural protein isn't going to remove the bad one,"
says Shy.
At this point, Shy and his Wayne State colleagues John Kamholz and Gyula Acsadi
have packaged the GDNF gene into viruses that can be used to safely deliver it
to muscles and nerves. They've shown that when the gene-laden viruses are
injected into mouse muscle, GDNF gets produced in the muscle, and taken up by
nerve cells connected to the muscle.
Their next goal, says Shy, is to test this method in mouse models of CMT and
amyotrophic lateral sclerosis (ALS), a paralyzing disease brought about by the
death of muscle-controlling nerve cells. "In both of these models, the basic
concept is figuring out how to prevent axonal degeneration," says Shy.
While Shy and his colleagues flesh out their gene therapy approach, the hunt for
CMT genes continues. But instead of just focusing on genes that can cause CMT,
investigators are starting to search for genes that can modify severity of the
disease, says Jeffery Vance. Evidence for such modifier genes comes from the
observation that individuals within a single CMT family can have very different
clinical features.
For other inheritable diseases, such as familial ALS, researchers are homing in
on modifier genes by studying mice. When mice that have a dominant ALS-causing
mutation are mated with inbred, healthy mice, some offspring inherit the
mutation but develop the disease significantly later than expected — suggesting
they've inherited beneficial modifier genes from their healthy parents.
Vance expects that researchers will soon use similar methods to track down
modifier genes that affect CMT, and says that his lab has begun to look for
such genes in humans. In general, modifier genes "hold real promise" for CMT
treatment, he suggests.
"If you understood how to modify the effect [of a defective gene], that's a lot
easier than trying to replace the gene." 
The Players
The seven identified CMT genes encode proteins that perform
essential (though in some cases unknown) functions in the peripheral nerves.
Though malfunction of any of the proteins can lead to CMT, the normal functions
of each protein appear quite different.
Myelin structural components
 Peripheral myelin protein 22 (PMP22) — CMT1(A), DS*, CMT4
Controls Schwann cell division?
 Myelin protein zero (MPZ, or P0) — CMT1(B), CMT2, DS*, CMT4
Holds layers of myelin together.
 Connexin 32 (Cx32, a.k.a. GJB1) — CMTX
Forms pores between layers of myelin.
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Transcription factors
(proteins that turn genes on or off)
 Early growth response gene 2 (EGR2, a.k.a. Krox20) — CMT1(C)
 Myotubularin-related protein-2 (MTMR2) — CMT4
 N-myc downstream-regulated gene 1 (NDRG1) — HMSN-Lom
All thought to regulate Schwann cell development and/or myelin formation, perhaps by controlling production of the above myelin components.
Axon structural components
 Neurofilament-light (NF-L) — CMT2 (single large Russian family)
Acts as backbone and conveyor belt within axon.
*DS =
Dejerine-Sottas
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