Hereditary Motor
& Sensory Neuropathy
Charcot Marie Tooth
I decided to put this information on my web page because my Wife and 2 Children suffer from H.M.S.N Type 1, along with another rare Genetic Disorder called Nail Patella Syndrome. Statistics indicate that both of these conditions are very rare, and the chance of finding one person with both conditions is practically impossible. There are 3 members of my family who have both of these conditions.
I hope you
find this information useful. Most of the information here has been extracted
from various sites on the net.
If you would like to know more, please.
Is the most commonly inherited disorder of the
peripheral nervous system, it affects the sensory and muscle control nerves of
the lower arms and legs.
Charcot-Marie-Tooth disorder or CMT is a disorder of the peripheral
nervous system that affects the sensory and motor nerves of the lower arms and
legs. For many years, it has been know that CMT is one of the few disorders,
which show all the known patters of inheritance (dominant inheritance, recessive
inheritance, and X-linked inheritance).
CMT is
also known as Peroneal Muscular Atrophy and Hereditary Motor Sensory Neuropathy
types 1 2 and X. The peroneal type of muscular atrophy was separated from the
other forms of progressive neuromuscular disorders in 1886 simultaneously by
the doctors, Charcot and Marie in France, and Tooth in the UK. It was Tooth who
first mentioned that out of the shin muscles of the leg, medically known as the
peroneus muscle, which lifts the foot (without it there is foot drop and severe
turning out) was affected by the disease. Therefore, Tooth called the disease
Peroneal Muscular Atrophy, a term which means the same as CMT disease.
In the beginning, Charcot and Tooth could not
agree what was affected by the disease Charcot said muscle, Tooth said nerve
and was later proved correct. The disease was therefore called a neuropathy.
The nerves affected were "Motor" those carrying messages to the
muscles and "Sensory" - those carrying messages from the extremities.
CMT is
the most commonly inherited disorder of the peripheral nervous system. As many
as 1 in 3000 people could have this disorder.
CMT in
most cases is an inherited disorder - although there are sporadic cases, which
have no family history of the disease.
The most common symptoms of the disorder are:
In the legs and feet
High arches of the foot
Hammer toes
High stepping gait - cause by foot drop
Wasting of the leg muscles resulting in poor
balance and circulation
In the arms and hands
Weakness of the hands generally
Weakness of the thumb muscle
Inability to manage fine co-ordination
Loss of sensation, resulting in cuts and burns
The condition is not life threatening and the
symptoms can be alleviated by physiotherapy, orthotics and sometimes surgery.
This is the most commonly autosomal dominant
inheritance. This means that each child of a CMT parent has a 50% chance of
inheriting the disorder. Sufferers of CMT Type I have slow nerve conduction
velocities.
Type I is comprised of Types a, b, and c (demyelinating
CMT, with slow nerve conduction).
CMT will cause various sorts of damage to nerves
depending on the type of disease. The loss of the insulating myelin reduces the
speed at which signals pass along the nerve, or reduction of nerve conduction
velocity, and this applies to CMT type I.
In autosomal dominant CMT Type Ia, the genetic
defect occurs in a duplication region on chromosome 17 in about 60-80% of cases
and the other CMT families do not have a microduplication; instead they have an
abnormal base pair substitution in the gene that produces the myelin protein
PMP-22. The gene (PMP-22) is known to lie within the microduplication as well.
About 95% of Type I people are located on chromosome 17.
The gene responsible for type CMT Ib has been
found on the long arm of chromosome 1. This type is caused by a genetic defect
in another protein, myelin protein zero (MPZ).
In CMT Type Ic there are few families with this
type and the chromosomal location is not known but the gene defects are not
found on either chromosomes 17 or 1.
When the nerve fibre itself (that is, not the
insulating material but the "wire") is affected by disease, the
signal will pass at normal speed but will be weaker than it should be,
resulting in the same effect as slow speed, the muscle still not moving
properly. CMT type II shows this feature and therefore the two types can be
distinguished from each other.
It should be pointed out that these problems with
the nerves cannot be repaired.
Most families with CMT II follow an autosomal
dominant inheritance pattern, which means that each child of a CMT parent has a
50% chance of inheriting the disease. About 40-50% of CMT2 families have their
genetic defect on chromosome 1, near the top and it is believed that at least 2
or 3 different genes cause this type of CMT.
The genetic defect occurs in the X chromosome.
All the female offspring of an affected male with X-linked CMT will be carriers
for CMT. Each daughter of a CMT mother will a 50% chance of being a carrier and
each son has a 50% chance of inheriting CMT.
The defect in X-linked CMT has been identified as
Connexin 32, a gap junction protein. X-linked CMT patients show a slow nerve
conduction velocity.
Usually both parents of an affected child are
clinically normal "disease carriers". This type of CMT is more common
in countries where the incidence of marrying close relatives is higher. The
parents have a 25% recurrence risk to have an affected child.
The gene for one of these forms, CMT4A is located
on chromosome 8 and it is probable that two other genes can cause Types 4B and
4C although the location of these types is not known. The genetic defect in
CMT4A is not yet known.
Therefore, with increased medical knowledge and
more sophisticated methods of Diagnosis, a wider range of symptoms became
apparent, and the name changed to keep up with this trend. The disease didn't
change, but doctors have become able to group people according to the new
techniques. This means a patient can be "typed". More recently, it
has been possible to break the disease down further into types, and these are
being used today. HMSN type 1A and 1B and II are the commonest.
What benefit is there knowing
what type I am?
An accurate diagnosis which allows the specialist
or experts to decide which type of CMT a patient may have is most useful for
family planning, or perhaps career planning. This is no easy task because HMSN
is highly variable even within one family.
The Function of the nerve
Motor function - this is the passing of a message
from the brain/spinal cord, down nerves to muscles to bring about a particular
movement. The message is passed in the form of an electrical signal. The nerve
consists of a long thread of fibre, which is insulated by a fatty substance
called myelin. Like any electrical wire, the conduction of the message is
dependent on the insulation being intact, if it isn't, the speed of conduction
is reduced, and the greater the damage, the slower the speed of passage of the
message, even to the point where signals fail to reach their destination.
This results in the muscles wasting away, since
they are not being told to move, and because the problem is located in the
nerves, exercising the muscles doesn't help a great deal. It should be noted
that this disease only affects what are called skeletal muscles, for instance,
the heart muscles and nerves are not affected, although the diaphragm is
connected to the nerve system and so can, in rare cases, be affected, though
not in a life threatening way.
Sensory function - electrical signals are passed
along the nerve in the same way as motor nerves but from joints or skin to the
spinal cord and are interpreted as sensation or feelings. Abnormal sensory
nerve function, therefore, causes loss of feeling, particularly in the hands
and feet.
Genetics
This is the scientific way of describing how
family features can be passed from one generation to another, a process known
as heredity. Every child will inherit some of its parent's features, some more
obvious than others - like hair and eye colour. The mixture of mother/father
features depends on the combination of chromosomes.
Chromosomes come in pairs and are packets of
codes, called genes. The codes carry all the messages that are needed to create
an individual eye colour, hair colour and sex. This of course, includes all the
instructions for the nervous system, as well as all the other
"mechanical" parts of the body. In CMT, the genes, which produce the
message to create the nervous system, are faulty, and therefore, cause the
problem.
Because there are many different types of CMT,
there is more than one faulty gene located on different chromosomes.
Researchers hope to be able to locate the different genes on the chromosomes,
and eventually find out what is wrong with those genes, since it is not known
what all the genetic faults are.
As mentioned previously, all genes are in pairs,
corresponding to the pairs of chromosome. When eggs and sperm are created, the
chromosomes split in half, so that each egg or sperm contains one gene out of
the pair. When fertilisation takes place, the chromosomes from the Mother and
Father form pairs again. Therefore, the offspring will have half the genes from
the Father and half from the Mother.
CMT types I and II, the most common types, are
inherited in the vast majority of cases as a dominant gene, the faulty gene
will take control out of the pair of genes. Therefore, when the chromosome
pairs split in half to create sperm or eggs, half will contain the faulty gene,
and half will be normal.
If a father has CMT type I - when his sperm
fertilises a normal egg (from an unaffected mother) - it is a fifty/fifty
chance as to whether the egg has been fertilised by a sperm containing the
faulty gene, or a normal one. Because the faulty gene is dominant, an egg
fertilised by this gene will produce a child with CMT type I as well.
CMT type III, and very rarely, some cases of CMT
I and II is inherited as a recessive gene. This means that the normal gene of
the pair is dominant, and therefore the faulty gene is inactive. In order for a
child to be affected, both parents must carry this inactive faulty gene on
their chromosomes. When the chromosomes split, half the chromosomes in the
sperm, and half in the egg will contain this faulty gene.
When fertilisation occurs, there are four
possible combinations of genes, the two normal genes will come together; giving
a normal child who doesn't have a faulty gene at all. There are two chances
that a normal gene will meet with a faulty one still creating a normal child,
because the normal gene takes precedence over the faulty one, but the child
carries the disease or the two faulty genes will come together, creating an
affected child, since there are no normal genes to suppress the faulty ones.
In other words, in the recessive forms of CMT,
there is a 1 in 4 chance of children being affected.
Even more rarely, the faulty gene is carried on
the special chromosomes, which determine the sex of the child, called X-linked
inheritance. Boys are more severely affected and they inherit the disease from
mothers with the faulty gene; the mother is either not affected or very mildly
affected. Each son will have a 50/50 chance of being affected, and each
daughter will have a 50/50 chance of being a carrier. The affected son then
cannot pass the disease onto his sons, but each daughter will be a carrier.
To Sum Up
HMSN is a group of inherited neurological
diseases - referred to as a syndrome. HMSN is part of the CMT
"syndrome" group. Damage to the nerve results in loss of muscle power
and disability. Nerves are damaged in two different ways - in CMT type I - the
insulating sheath of the nerve is lost, and in CMT type II - the nerve fibre
itself is damaged.
Inheritance is usually dominant which means there
is a 1 in 2 chance that a child will inherit the disease from an affected
parent.
Here are some links to CMT related sites.
CMT International
Charcot-Marie-Tooth
Association