Dr. Dyck discusses CMT (and hope)

[Guest guest]

Dr. Dyck discusses CMT (and hope)

The following article is excerpted from the keynote address Dr.

Dyck gave at the Second International Conference on Charcot-

Marie-Tooth disorders in June, 1987. The conference was sponsored by

the NFPMA and Columbia University. (See The NFPMA Report, Vol. 1,

#3.)

My interest in inherited neuropathy began in 1962. I began to see

patients in a valley of the Mississippi River, the Zumbro River,

which flows into Lake Pepin. This kindred lived in the small

villages and farms of that area and it turned out that investigators

from the University of Minnesota had done genetic studies in this

region some fifty years earlier.

I pursued Ed Lambert's discovery of low nerve conduction in inherited

neuropathy. We now know much more about inherited neuropathy than

we did twenty-five years ago. Unfortunately much more remains to be

discovered about inherited neuropathy. When we began our studies the

question was why are conduction velocities low in inherited

neuropathy? Lambert had made the observation that they sometimes were

low, and secondly that they might serve as a marker of Charcot-Marie-

Tooth syndrome.

We asked a series of questions. Why was nerve conduction low? Did

all kindreds with peroneal muscular atrophy have such low nerve

conductions? Are the nerves enlarged in peroneal muscular atrophy?

Why?

Since nerve has fibers of different functional and size classes,

which classes were especially vulnerable to disease? Was the neuron,

or the axon, or the Schwann cell, or the myelin selectively

involved? What were the three dimensional alterations along the

nerve fiber? We also asked what was the metabolic abnormality in

these diseases?

Were the syndromes with peroneal muscular atrophy distinctly

different? Were they from different mutant genes? What was the role

of environmental factors? What were the gene loci (chromosome

locations)? Are there specific treatments in these disorders? The

reason for listing these questions is to show that progress has been

made in the last twenty-five years. We have answers for many of

these questions.

Since I began my studies in inherited neuropathy we have learned a

lot. We know that peroneal muscular atrophy is not one disease but

several diseases. We have learned a considerable amount about how

the disorders can be detected and characterized. The disorders known

as Charcot-Marie-Tooth syndrome may also be referred to as forms of

Hereditary Motor and Sensory Neuropathy, or HMSN. Some are directly

inherited from an affected parent to one-half of the children

(dominantly inherited). Others are recessively inherited (25% of the

children from unaffected parents) and still others are inherited

(sons) from an unaffected mother (sex-linked). There are different

disorders

even within these different inheritance patterns. Low nerve

onductions are a useful marker for some disorders but not for

others. The approximate chromosome and gene localization is known

for two varieties of HMSN, HMSN-lb and sex linked HMSN.

We now have some understanding of the structural changes in nerve

which account for the clinical symptoms and abnormality of nerve

conduction. In HMSN-1 all classes of nerve fibers are affected.

There is an abnormality of redistribution of enzymes and other

macromolecules along the length of the fiber. The nerve fiber

appears to develop normally, then prematurely begins to atrophy.

This atrophic condition appears to begin in the feet and legs. With

atrophy there is myelin remodeling. Repeated de- and remyelination

is involved in developing a microscopic abnormality called the onion-

bulb

formation and enlargement of the nerve. Disturbed electrical

phenomena are associated with fiber atrophy and myelin re-modeling.

Low nerve conductions, in general, relate to the severity of the

clinical deficits. The evidence for myelin remodeling and for the

occurrence of secondary demyelination also came from studies of

uremic neuropathy, Friedreich's Ataxia (a recessively inherited

disorder also associated with peroneal muscular atrophy) and an

experimental study of the nerves above the site of the amputation of

the legs in cat and man.

Several lines of evidence convinced us that demyelination (breakdown

of the fat and protein insulation of a nerve fiber) could, in some

cases, be due to axonal atrophy. The reasons were: (1) demyelination

was clustered on certain fibers-presumably those with atrophic axons,

(2) demyelination was more frequent in more proximal aspects of nerve-

distally fibers had undergone degeneration, and (3) in transverse

sections of nerve the caliber of axons relative to myelin thickness

was decreased as compared to normal.

To prove our hypothesis we amputated legs of cats and evaluated nerve

fibers above the amputations at various times after injury. Even by

four months the frequency distribution peaks of myelin fiber

diameters had shifted to smaller diameter categories. By one year

this atrophic trend was clear. By two years the findings were very

striking; an atrophic process had occurred. We could reproduce all

of the changes that we had seen in uremic nerves. After injury the

following sequential changes had taken place: axonal atrophy,

myelin wrinkling, paranodal or internodal demyelination,

remyelination, and with further atrophy axonal degeneration. Our

model had proven what we had suspected from the human observations.

Axonal atrophy may cause myelin remodeling.

A new insight which has come from our recent studies is the important

role of environmental factors in the clinical manifestations of

HMSN. This should not have been a surprise since it was already

clear from both experimental study and human neuropathy that

environmental factors do play a role in the expression of mutant

genes. For example, in porphyria the clinical disorder is not

expressed until you give the patient a barbiturate.

In the case of Refsum's disease, a peroneal muscular atrophy with

excessive storage of phytanic acid, deleting phytanic acid from the

diet can improve nerve function. So in those two genetic diseases,

there is clear evidence that the environment does make a difference.

It may also make a difference to the symptoms of HMSN neuropathy.

We have not talked about this yet, but physicians should make very

careful distinctions between the symptoms which a patient has, the

deficits which he has and the accompanying neurophysiological

abnormalities. The physician should further make a distinction

between conduction velocity on one hand and abnormalities of

amplitude and distal latency on the other hand. They do tell you

different things. Even though there is an association among them,

they do represent different pathophysiological mechanisms,

obviously related.

Let's deal with the issue of burning feet. When I first began to see

patients with burning feet, it often occurred to me that perhaps they

were neurotic patients, old age patients who had hurting feet and

were complainers. But as I began to see these patients, I recognized

that sometimes their symptoms were inherited. When I studied some of

the older members of such a family, there was unequivocal evidence of

neuropathy.

That was an important insight for me because here the deficit was not

the problem, but the symptom was a major problem. A secretary from

Phoenix, AZ came to see me because of burning feet without evidence

of neuropathy. We did extensive autonomic and other tests and even

nerve biopsy, all of which were normal. Her father, however,

who had had burning feet, clearly had some signs of the

electrophysiological abnormality of neuropathy, as did an uncle.

The issue which was of such great interest to me was that

environmental factors related to that symptom. For example, if the

girl was in Minnesota, where it's cool and wonderful and placid, she

did not have burning feet. In Arizona, where it's hot and they have

only asphalt, she had a lot of pain. In other words, the thermal

condition which her feet were exposed to affected her symptoms. Her

uncle who plowed the fields found that he could get relief for his

symptoms by taking off his shoes and walking in the cold furrow. In

the winter time he would put his feet up against the wall to get

relief.

So think carefully when you see a patient with these symptoms,

because you might be able to ameliorate them. I have had patients

coming from San Francisco who ran twenty miles a day. By reducing

that to five miles a day they can live with their feet with their

mild inherited neuropathy. So mechano-sensitivity is something you

can modulate...it's an important issue, I think, that we should be

thinking very carefully about modulation of neurophysiological

activity which may give symptoms.

Sabin and Swift had a patient with leprosy, lepromatous leprosy.

That is sensory loss in both hands. The man developed a stroke, so

one arm was paralyzed. It was the other arm that developed the

mutilating acropathy.

So here was an example of a patient who had the same degree of

sensory loss bilaterally, but it was the use and abuse that led to

the complications. So quite a different idea came to me about how

people develop the mutilation. ... Not only is it the sensory loss,

which

may be trivial, but it's how you use your limbs, what precautions you

take, whether you are indifferent to your injuries and whether you

neglect trivial injuries. So you have an accumulation of trivial

injuries which lead to these terrible complications. That is where

all of us come in, because these are preventable troubles. Some of

the major complications, the plantar ulcers, the Charcot joints are

preventable. The patients who have inherited neuropathy should know

that this is a failure of taking proper precautions.

In the Quebec and Virginia kinships that we studied, we found that it

was the males that had the problem. The women looked after their

feet, they did not walk in the frozen nights of Virginia and the

crates of chickens did not fall on their feet. The outcome was

strikingly different due to different environmental factors, but the

sensory loss was the same. So a very important message to patients

and to us: prevent these kinds of complications. The environment

does influence the expression of these genetic abnormalities by what

we do and what we advise. We wrote an article on the factors that

may be involved.

I want to end up with what one tells the patient with inherited

neuropathy. First of all, tell the truth. When I first began as a

neurologist at Mayo Clinic I asked Millikin, " What do I do? "

He said, " Tell the truth. " That is not bad advice. I find that many

physicians are kind of playing games with patients and there is no

reason why you cannot tell the truth. The truth is generally better

than the anticipation of an anxious patient.

Second point: tell the patient about the disorder. Tell them what

you know. When you do not know, say, " I don't know what you have. "

If you think the patient has inherited neuropathy, tell the patient

what you need to do to be sure. A little candor can go a long way.

Tell them about the outlook. Some physicians follow the practice of

sending the child out of the room while the disease is discussed with

the parents. Don't do this! This practice sends the child a message

that he must have something terrible that can't be talked about with

him present. You can always talk about the outlook of a disease if

you do it honestly. Many physicians paint much too gloomy a

picture. They have been brainwashed by the textbooks. The textbooks

tell the worst story. The truth is usually better than the textbooks

by a long shot. You may have noticed that our slides, our textbook

pictures showed only the worst cases, but 95% of cases have less

abnormality than demonstrated in lectures and chapters.

Tell them about the outlook. The outlook is excellent in most

cases. They can go to school, they can marry, they can have

children. Why not? Why should they not have children? Some of the

best people I have known have Charcot-Marie-Tooth disease. Tell them

about what they should do. In my experience, they all want to be

geologists or foresters. Well, try to persuade them to pursue other

jobs. They should go to school and learn something else which also

would be worthwhile, besides it might be fun.

Tell them about how their disease is inherited. Do not go simply by

the phenotype; base it on the examination of the relatives. You may

need to examine the parents, the children, the uncles, and the

aunts. Get them to come in. Do not get someone in San Francisco to

do it, do it yourself.

If you do not adequately advise about inheritance, a legal problem

may ensue. I have known of cases where doctors have told patients

that they had an inherited neuromuscular disease but have failed to

provide enough information about the implications for the

descendants. The physician could be perceived as having been

negligent if insufficient information was provided. To be the

genetic advisor the neurologist should be able to explain Mendelian

inheritance and the probability of involvement among offspring.

Remember that in dominantly inherited HMSN-la and -b and also in HMSN-

11, although the probability is that 50% of offspring of a person

with the disorder will be affected, a lesser percentage will have the

severity of involvement that the parent has. On average the affected

children are going to be less affected than the affected parent.

That's good news.

Physical fitness. Although we are all going to do the definitive

study and Wally Bradley has just told me about an excellent design,

we know that physical fitness is good for patients, have had HMSN

patients who were the tennis champ of Indiana or the winning

bicyclist of Iowa. They seem to have clearly helped themselves with

exercise. Physical fitness also helps control weight.

Diet. There is no evidence that diet has anything to do with this

disease. So, except for the amount of calories, there is no

information.

Vitamins. Don't waste your money; it's been tried for fifty years.

It never did any good. Unless you are B-1 2 deficient, are a

lactating mother or were a prisoner of war, you do not need exogenous

vitamins. Excessive B-6 vitamin can cause neuropathy!

Ultimately, the point I want to make is to provide hope. That is

what being a physician is about. When you talk to patients with this

disorder, tell them that for most patients with HMSN the life

expectancy is normal. Some of the life insurance companies do not

seem to be aware of this fact! The fact is that life expectancy for

most of these patients is normal. There are many worthwhile things

to do. " Ask not what the country can do for you, but what you can do

for the country. "

Most patients with HMSN should hold jobs. Many patients with HMSN

are too concerned about their disease. There are some mighty

good things they can do for others, and it also minimizes their

concern about themselves.

Tell them you don't want to see them for ten years, no, twenty

years. You see, what that tells them is that they are not on a

precipice, they are not about to fall off. Yes, you will see them in

a year, but get across the idea that there is nothing to be alarmed

about.

There is hope in that the people here are going to tell us where the

CMT genes are, and are going to find the specific proteins, and are

going to find the specific treatment for the disease. So there is

considerable hope that the causes of HMSN will be delineated in the

next few decades and good prevention and treatment will become

available. Already there is a great deal that can be done

symptomatically!