Types of CMT website

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Types and Causes of CMT

The nervous system consists of motor neurons and sensory neurons. One set of

nerves carries messages from the brain outward to the rest of the body and

one brings messages from the extremities back to the brain. Messages that

travel from the brain down the spinal cord, through the lower motor neurons

(such

as the sciatic nerve of the leg) to the muscles of the body are part of the

motor neuron circuitry. Messages that travel upward from the sensory input to

the spinal cord and finally the brain are sent by sensory neurons.

The peripheral nervous system is also comprised of motor and sensory nerve

fibers, and since CMT affects the peripheral nerves, it results in both motor

symptoms (weakness and muscle wasting) and sensory symptoms (numbness). The

peripheral nerves are often described as being like electrical wires with an

inner core (the axon), which is wrapped in insulation (a sheath called myelin).

When the myelin is damaged (Type 1 CMT), the nerve impulses are conducted

more slowly than normal. If the axon itself is damaged (Type 2), the speed of

nerve conduction is almost normal, but the strength of the signal is reduced.

All forms of CMT are either demyelinating or axonal in nature. Since CMT is a

multi-gene disorder, there are many different defective genes which cause

the disorder. Since 1991, more than 30 different genes causing CMT have been

identified and the loci are known for at least another ten causes. The ones

that have been identified to date are:

CMT Type 1

With the exception of Type 1X, which is inherited through the X Chromosome,

CMT Type 1 is inherited in an autosomal dominant pattern. (See _inheritance_

(http://www.charcot-marie-tooth.org/about_cmt/genetics.php) .) CMT Type 1

accounts for more than two-thirds of all cases of CMT.

Type 1A

This is the most common form of CMT, comprising at least 60 percent of all

patients with CMT Type 1. The disorder is caused by a duplication of the PMP22

gene on Chromosome 17. Instead of having two copies of the gene (one of each

paired chromosome), there are three copies, two on one chromosome and one on

the other. PMP22 is a peripheral myelin protein, but its exact function in

causing CMT is still not known. It is inherited in an autosomal dominant

fashion.

CMT1A usually presents with a typical CMT phenotype (clinical presentation).

Patients are slow runners in childhood, develop high arches, hammer toes and

often require orthotics (braces) for ankle support. Varying degrees of hand

weakness occur, often appearing as much as ten years after foot and leg

problems. Problems with balance because of ankle weakness and loss of

proprioception are common. Most patients remain ambulatory throughout life and

life

expectancy is normal.

Type IB

This type is caused by a defect of the MPZ gene on chromosome 1. Again, MPZ

is peripheral myelin protein, but its role is not known. Type 1B is an

autosomal dominant disorder. Patients with 1B have a somewhat typical

phenotype, but

often with more pronounced calf wasting. There is a wide range of severity

within Type 1B, from very severe forms such as Dejerine-Sottas (infantile

onset) to milder cases with onset much later in life. (More than one type of

CMT

may be referred to as Dejerine-Sottas since the term refers to an age of

onset of less than three years rather than to a unique genetic defect.)

Type 1C

Researchers at the University of Washington have recently identified the

locus of Type 1C as Chromosome 16, the LITAF/SIMPLE gene. Type 1C is also

autosomal dominant in inheritance. There is limited clinical information on

patients with 1C, but they develop distal weakness, atrophy, and sensory loss

and

have slow nerve conduction velocity scores.

Type 1D

This type is caused by an early growth response protein 2, known as ERG2,

found on Chromosome 10. Inheritance is autosomal dominant. Most cases of 1D are

severe, such as Dejerine-Sottas, while a few have milder phenotypes

presenting later in life.

Type 1F

Type 1F accounts for a very small percentage of cases. It is an autosomal

dominant form of CMT in which the defect is on Chromosome 8 and the

neurofilament light chain protein.

Type 1X

This second most common of form of CMT, accounting for 10-16 percent of all

cases is found on the X Chromosome, one of sex chromosomes. The flaw is caused

by a gap junction beta 1 protein connected to connexin 32. Typically, this

form has onset in adolescence or childhood and often affects males more

severely than females. An affected male with CMT1X cannot pass the defect to

his

son, but will pass it to all his daughters. An affected female has a 50% chance

of passing the mutation to either her sons or her daughters.

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

HNPP is also inherited in an autosomal dominant pattern and is also located

on Chromosome 17 at the PMP 22 gene, as is Type 1A. The difference is that

there is a deletion rather than a duplication at the gene site. Clinically,

HNPP

defers from CMT in that patients with HNPP typically have transient episodes

of weakness or sensory loss, which can last from hours to days. Thickening

of myelin is the hallmark of HNPP. (See _More About HNPP_

(http://www.charcot-marie-tooth.org/about_cmt/hnpp.php) .)

CMT Type 2

CMT Type 2 represents axonal forms that are dominantly inherited and make up

about one-third of all dominant CMT cases. The clinical presentation is

similar to Type 1: distal weakness, muscle atrophy, sensory loss and foot

deformities. Patients with Type 2 have a wider age range for onset of the

disorder

and more variation in degree of disability. They are slightly more likely to

maintain their deep tendon reflexes.

Type 2A

The defect causing CMT 2A is found on chromosome 1p36 at the MFN2 gene. This

gene is mutated and is involved in the fusion of mitochondria, the metabolic

engines of the cells.

Type 2B

Type 2B is characterized by severe ulceration problems and the defect is

located on chromosome 3, the RAB 7 protein. CMT 2B is predominantly a sensory

disorder and there is some thought that it is not really CMT, but a pure sensory

neuropathy.

Type 2C

This type is a very rare form in which patients may have diaphragm or vocal

cord paresis in addition to the other problems of CMT. Linkage to chromosome

12 has been found.

Type 2D

The CMT 2D locus is on chromosome 7p14 and the genetic cause has been

identified as mutations in the glycyl RNA synthetase gene. CMT 2D is a confusing

disorder because some patients have sensorimotor neuropathies, while others have

only motor symptoms.

Type 2E

CMT type 2E has been established with linkage to chromosome 8p21 and studies

have identified mutations in the neurofilament light gene.

CMT Type 3

Type 3 is a particularly severe variant. The term Dejerine-Sottas syndrome

(DSS) is used to describe patients who are severely disabled and develop CMT in

infancy. This term was coined before the genetic causes of CMT were

identified. As a result, the usage of this term is somewhat confusing.

Dejerine-Sottas was originally thought to be a severe and disabling neuropathy

beginning in

infancy with an autosomal recessive inheritance pattern. Recently, it has

been shown that DSS patients also have autosomal dominant mutations of PMP22,

MPZ, EGR2 and even PRX and GDAP. Most patients with DSS have extremely slow

nerve conduction velocities. Most children with DSN have severe demyelination

while others show predominantly axonal loss when sural nerve biopsies are

done. Currently, the term Dejerine-Sottas is used to define patients who have

onset by 3 years of age, delayed motor milestones, and severe motor, sensory

and

skeletal defects.

Congenital hypomyelination (CH) is a term originally used to describe

peripheral nerves that were so abnormal that they suggested a developmental

failure

of the peripheral nervous system myelination. Patients with CH were

hypotonic within the first year of life, had developmental delays in walking and

had

swallowing or respiratory difficulties. Some patients with CH were considered

“floppy†infants. It is difficult to distinguish between DSS and CH since

both have severe pathological changes on sural nerve biopsies and both have

very slow nerve conduction velocities.

CMT Type 4

All Type 4 instances of CMT are inherited in an autosomal recessive pattern

and are considered rare. They have various phenotypical presentations but are

more severe than autosomal dominantly inherited disorders. These disorders

often have systemic symptoms, such as cataracts and deafness. CMT 4A and B are

demyelinating and 4C is axonal.

Type 4A

CMT Type 4 is linked to Chromosome 8 and is caused by mutations in the GDAP 1

protein, of unknown function. This form was first described in four families

in Tunisia who were highly inbred. Clincial onset began at age 2 with

delayed developmental milestones of sitting or walking. Many patients are

wheelchair dependent by the end of the first decade of life. Hoarse voice and

vocal

cord paresis have been reported.

Type 4B

The genetic location for the defect causing Type 4B is on chromosome 11 and

presents with focally folded myelin sheaths in nerve biopsies. Affected

patients become symptomatic early in life, with an average age of onset at 34

months. Unlike most types of CMT, both proximal and distal weakness is common.

Type 4C

Type 4C is a childhood onset form of hereditary motor and sensory neuropathy

(HSMN) with early onset scoliosis. The protein defect defines a new family of

unknown function.

Type 4D

This form was first described as a separate disorder with linkage to

Chromosome 8 in a Gypsy population with autosomal recessive inheritance. The

clinical features included distal weakness, muscle wasting and sensory loss,

foot

and hand deformities and loss of deep tendon reflexes. Deafness is always found

in these patients and occurs by the third decade. Nerve conduction is

severely reduced in younger patients and completely unattainable after age

15.Type

4F

CMT type 4F is a severe form of recessive CMT that has been defined in a

large Lebanese family with mutations in the PRX gene on Chromosome 19. Nerve

conduction studies are markedly slow and onion bulb formations are observed in

nerve biopsies.

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Thank you for explaining the different CMT types so it can be easily

understood. I for one REALLY appreciate it.

Barb