Quest article

[Guest guest]

For those of you who can't get to the internet, or don't want to, here are a

few of the points made by the Quest article:

http://www.mdausa.org/publications/Quest/q81cmtds.cfm

The renowned 19th-century French neurologist Jean- Charcot advised

young scientists that they should be prepared to deal with complex origins

and manifestations of disease. But even he couldn't have predicted the hidden

complexity of a disease he helped to discover — Charcot-Marie-Tooth disease

(CMT).CMT — first described by Charcot and his contemporaries Pierre Marie

and H.H. Tooth in 1886 — causes weakness by damaging nerves that are required

for muscle control, and is the most common inherited disorder of the nervous

system.

Despite its remarkable history and prevalence, CMT has no treatment, and its

genetic origins were completely unknown until 1992.

The search for a genetic cause of CMT began in the mid-1980s. Around that

time, researchers had discovered that Duchenne/ Becker muscular dystrophy

(DMD/ BMD) was caused by defects in a single gene. The same is true in both

Huntington's disease and cystic fibrosis. In each case, the discovery of a

single disease gene provided a key for understanding disease pathology and

for designing possible treatments that are currently being tested.

Those successes provided CMT researchers with the technical advances and the

optimism they needed to hunt for a CMT gene, but they didn't anticipate a

simple resolution. By the 1970s, several types of CMT were recognized based

on characteristic features of the disease within different families. So,

researchers weren't expecting to find just one CMT gene.

But they've been stunned by the number of CMT genes their search has

uncovered. As is the case for Huntington's, DMD/BMD and cystic fibrosis, a

single defective gene can cause CMT in one person. But there appear to be at

least 18 CMT genes among the world population. So far, seven of these CMT

genes have been identified, and 11 more are suspected.

Although CMT is more complex than Charcot could have imagined, modern

researchers are now beginning to unravel that complexity. Studies of CMT

genes and their functions are leading to a better understanding of how nerves

work, how they become damaged in CMT and how to protect them from damage.

Despite its diverse genetic origins, CMT is universally recognized as an

inherited disorder that affects the peripheral nerves — nervous tissue that

connects the spinal cord to the muscles and sensory organs. Its defining

symptoms are muscle weakness and wasting, and usually some loss of sensation,

in the body's extremities (the forearms, lower limbs, hands and feet). Often,

these symptoms appear in adolescence.

Because of these features, CMT is sometimes called hereditary motor and

sensory neuropathy or HMSN (a neuropathy is any disease of the peripheral

nerves). CMT also has a more old-fashioned name — peroneal muscular atrophy

— which refers to wasting of the peroneal muscle in the lower leg.

Usually, CMT isn't life-threatening. But it can cause significant disability,

including difficulty with routine activities like walking and grasping

objects. Sometimes, a person with CMT requires braces or a wheelchair for

mobility. The muscle weakness of CMT can cause deformities of the hands and

feet, and the loss of sensation can cause minor foot injuries to go

unnoticed, sometimes leading to infected sores called ulcerations. In severe

cases, the ulcerations might require amputation.

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CMT1A and HNPP: Flip Sides of the Same Coin

In the late 1980s, while the CMT gene hunt was gaining momentum, neurologist

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...

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.

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Kat

[Guest guest]

Hey Gretchen,

I saw the article in Quest today when I was waiting for the Doc at the

MDA clinic. Funny, I didn't even know what you looked like before today - do you

have a pic posted at the group site? <Slaps forehead> I didn't even thin kto

look! LOL I just wanted to commend you on being brave enough to tell your

story about substance abuse; I don't think I could have been that open. But I

guess that's part of what makes all of us different, right? Anyway, I just want

to

say that you are a very beautiful person, and now I know it is more than just

on the inside ;o) Have a wonderful day, - Born & Raised Okie