Fw: CMT Type 2/TO JR.

August 31, 2000

-----Original Message-----

From: Maxwell <rmax@...>

Maxwell <rmax@...>

Date: Wednesday, July 05, 2000 3:21 AM

Subject: CMT Type 2

Jr. please read this. Notice where it says The diagnosis IS based on clinical

and EMG/NCV caracteristics.

Charcot-Marie-Tooth Type 2

[CMT2, Hereditary Motor and Sensory Neuropathy(HMSN2), Peroneal Muscular

Atrophy. Includes:

Charcot-Marie-Tooth Disease, Neuronal Type; Charcot-Marie-Tooth Disease, Axonal

Type; CMT2A; CMT2B;

CMT2C; CMT2D]

Author: TD Bird, MD

Update: 15 June 2000

Summary

Disease characteristics. CMT type 2 is a syndrome of autosomal dominant

non-demyelinating peripheral

neuropathy associated with distal muscle weakness and atrophy, mild sensory

loss, and normal nerve conduction

velocities. The condition is clinically similar to CMT1, although typically less

severe. Peripheral nerves are not

enlarged or hypertrophic. Several genetic subtypes have been identified by

linkage analysis, but no

disease-causing genes have been identified.

Diagnosis. The diagnosis is based on clinical and EMG/NCV characteristics. No

diagnostic genetic tests exist.

Genetic counseling. CMT2 is autosomal dominant and each child of an affected

individual is at 50% risk.

Diagnosis

CMT type 2 is diagnosed in patients with a progressive peripheral motor and

sensory neuropathy with normal or

near-normal nerve conduction velocities (NCV) that is inherited in an autosomal

dominant manner. The four

subtypes of CMT2 are indistinguishable clinically and are distinguished solely

on genetic linkage findings. The

relative proportions of CMT2A, 2B, 2C and 2D are yet to be determined. The

chromosomal loci for CMT2A, CMT2B,

and CMT2D have been mapped, but the genes have not been identified. DNA-based

testing is not available

clinically. Linkage testing for CMT2 is performed on a research basis only.

Clinical Description

CMT2 is a genetic disorder of peripheral nerves in which the motor system is

more prominently involved than the

sensory system, although both are involved. The typical patient has slowly

progressive weakness and atrophy of

distal muscles in the feet and/or hands usually associated with depressed tendon

reflexes and mild or no sensory

loss. The NCVs are normal or mildly slow (30-40m/s), but the EMG is abnormal,

with such findings as positive

waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked

motor and sensory responses [Dyck

et al 1993, Nicholson 1991, Dyck et al 1994].

Patients usually become symptomatic between ages 5 and 25 years [ et al

1995, Saito 1997, Berciano

1986]. However, earlier onset with delayed walking in infancy as well as later

onset in the fourth and subsequent

decades certainly occur. The typical presenting symptom is weakness of the feet

and ankles. The initial physical

findings are depressed or absent tendon reflexes with weakness of foot

dorsiflexion at the ankle. The typical adult

patient has bilateral foot drop, symmetrical atrophy of muscles below the knee

(stork leg appearance), less

frequent atrophy of intrinsic hand muscles, and absent tendon reflexes in lower

extremities that may be intact in

the upper limbs [Dyck et al 1993]. Proximal muscles usually remain strong. Mild

sensory loss including deficits of

position, vibration, and pain/temperature may occur in the feet or sensation may

be intact. Pain, especially in the

feet, is reported by about 20% of patients.

A few patients have vocal cord or phrenic nerve involvement resulting in

difficulty with voice or breathing. CMT2 is

progressive over many years, but patients experience long plateau periods

without obvious deterioration. In some,

the disease can be extremely mild and go unrecognized by patient and physician.

The disease does not decrease

life span.

Nerve conduction velocities are usually within the normal range, although

occasionally they fall in the low normal or

mildly abnormal range as noted above [Dyck et al 1993, Saito et al 1997]. EMG

testing shows evidence of an

axonal neuropathy. Nerve biopsies do not show hypertrophy or onion bulb

formation but instead show loss of

myelinated fibers with signs of regeneration and atrophic axons with

neurofilaments [berciano 1986, Ono 1993].

The disease process is presumed to be occurring in the axon or cytoplasm of the

anterior horn cell neuron and

anterior horn cell loss has been found in two reported autopsies [berciano 1986,

Ono 1993]. The clinical syndrome

overlaps extensively with CMT1, although, in general, the CMT2 patients tend to

be less disabled and have less

sensory loss (except for CMT2B; see below).

There are several different types of autosomal dominant hereditary axonal

neuropathies that may cause

predominantly sensory symptoms, including a family with the " burning feet

syndrome " [stogbauer et al 1999].

Genotype-Phenotype Correlations

CMT2A is the " typical " type of CMT2 described above. CMT2B has prominent sensory

loss with distal ulceration and

controversy regarding its exact classification exists [DeJonghe et al 1997a,

Elliott et al 1997]. Another form of

dominant motor and sensory neuropathy from Okinawa has been mapped to 3q13

[Takashima et al 1997, 1999].

The relationship of this entity to CMT2B linked to a similar region is

undetermined. CMT2C is associated with vocal

chord and phrenic nerve paralysis [Dyck 1994]. CMT2D has prominent weakness and

atrophy of the hands

[ionescu 1996].

The CMT2 phenotype with only mild slowing of NCV is sometimes caused by

mutations in myelin P0 (MPZ) including

a single mutation that has occurred in several families (Thr124Met) [senderak et

al 2000]. The same mutation has

also been associated with the CMT2 phenotype with deafness and Argyll on

pupils [Chapon et al 1999].

The CMT2 phenotype can also occur in families with CMTX (connexin-32 mutations),

but such families do not show

male-to-male transmission [Gutierrez et al 2000].

Prevalence

The overall prevalence of hereditary neuropathies is estimated to be

approximately 30 per 100,000 population.

About 30% of these cases may be CMT type 2 (10 per 100,000).

Differential Diagnosis

Note that CMT2 can sometimes be difficult to distinguish from CMT1 and CMTX

[Timmerman 1996] and from

chronic idiopathic axonal neuropathy [Teunissen 1997]. It is always important to

exclude potential causes of

acquired neuropathy (see CMT Overview).

Management

No treatment for CMT that reverses or slows the natural disease process exists.

There are many symptomatic

treatments and patients are often evaluated and managed by a team that includes

a neurologist, physiatrist,

orthopedic surgeon, and physical and occupational therapists [ et al

1995]. Daily heel cord stretching

exercises to prevent Achilles' tendon shortening are desirable. Special shoes,

including those with good ankle

support, may be needed. Patients often require ankle/foot orthoses (AFO) to

correct foot drop and aid walking

[Dyck et al 1994, et al 1995]. Orthopedic surgery may be required to

correct severe pes cavus deformity.

Some patients require forearm crutches or canes for gait stability, but less

than 5% of patients need wheelchairs.

Obesity is to be avoided because it makes walking more difficult. Exercise is

encouraged within the patient's

capability and many individuals remain physically active. Important career and

employment implications may exist

because of the persistent weakness of hands and/or feet. Drugs and medications

such as vincristine, isoniazid,

and nitrofurantoin that are known to cause nerve damage should be avoided [Graf

et al 1996].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with

information on the nature, inheritance,

and implications of genetic disorders to help them make informed medical and

personal decisions. This section

deals with genetic risk assessment and the use of genetic testing to clarify

genetic status. It is not meant to

address all personal or cultural issues that individuals might face or to

substitute for consultation with a genetics

professional. To find a genetics or prenatal diagnosis clinic, see . ?ED.

Mode of Inheritance

All four subtypes of CMT2 are inherited in an autosomal dominant manner. There

are axonal forms of CMT that are

inherited in an autosomal recessive manner. These recessive forms are described

in the profile on CMT4.

Risk to Family Members

Most individuals with CMT2 will have inherited the gene from an affected parent.

It is appropriate to evaluate the

parents of an individuals with CMT2 in order to determine which, if either, is

symptomatic, both to assure

appropriate medical management for that individual and for genetic counseling of

the family. Occasionally neither

parent will show signs of the disorder. Reasons for this include failure to

recognize mild symptoms in a parent who

has the mutated gene, a new gene mutation in the index case, and false

paternity. Affected individuals have a

50% chance of passing the CMT2 gene on to each offspring. No genetic test to

detect CMT2 is available.

Asymptomatic adults at risk of having inherited a CMT2 gene may wish to pursue

further clinical evaluation and

NCV testing. No treatment is available to individuals early in the course of the

disease. Thus such testing is for

personal decision making only. Testing children at risk who are asymptomatic is

not appropriate. (See also the

National Society of Genetic Counselors statement on genetic testing of

children.)

Prenatal Testing

Before considering prenatal testing, its availability should be confirmed. Note:

Prior testing of family members is

usually necessary. ?ED.

Prenatal testing to detect CMT2 is not available.

Molecular Genetics

Table 1. Molecular Genetics of CMT2

Disease

Name

Inheritance

Proportion

Gene

Symbol

Locus

Normal

Gene

Product

Testing

Genomic

Databases

CMT2A

AD

Unknown

CMT2A

1p36-p35

Research

CMT2B

AD

Unknown

CMT2B

3q13-q22

CMT2C

AD

Unknown

CMT2C

?

CMT2D

AD

Unknown

CMT2D

7p14

CMT2

(MPZ

mutations)

AD

Unknown

MPZ

1q23

Myelin P0

Clinical

CMT2A links to chromosome 1p [ben Othmane et al 1993], CMT2B links to 3q [De

Jonghe et al 1997a], and CMT2D

links to 7p [ionescue et al 1996]. CMT2C refers to two families with autosomal

dominant axonal neuropathy

associated with frequent vocal cord and phrenic nerve paralysis sometimes

requiring tracheotomy [Dyck et al

1994]. The condition does not link to the CMT2A or CMT2B loci. Other families do

not show any of these linkage

relationships and represent further genetic heterogeneity within the CMT2

phenotype. The frequencies of the

various types of CMT2 are unknown and no single type is known to predominate

[Timmerman et al 1996].

Resources

GeneClinics provides information about selected national organizations and

resources for the benefit of the

reader. GeneClinics is not responsible for information provided by other

organizations. ?ED.

September 1, 2000

Hello Becky,

That was a great article. I am going to print it out! I believe it restates

what I was saying about EMG testing, however please do not take this wrong,

it is a very good and important test, without it DR's have no clue what is

happening, they have not yet ID all the DNA test needed to get quicker and

more accurate diagnosis. You " guys " are the greatest! You have so much

information for me! If you think I need to be put in my place just put me

there OK? Do you have severe pain with type 2 as I do with type 1?

Thanks again Becky, have a wonderful day! jr

September 1, 2000

In a message dated 9/1/00 1:52:43 PM, liliwigg@... writes:

<< OK? Do you have severe pain with type 2 as I do with type 1? >>

I'm not JR, but I believe my pain is as severe as many type 1 CMTers have.

I've always been a stoic about pain, but my husband hears my involuntary

gasps and groans from my wrenching spasms and " bee stings " all thru the day

and night. Those are my current worst pains. My pain is nerve pain, not

structural pain. My neuro knew what I was talking about as soon as I started

to describe it. He was not surprised nor doubtful.

I have type 2.

I read a number of type 2 responses about severe pain.

Kat

September 1, 2000

JR,

Lamar here,

I do not have Type 1, HNPP, or X-linked, so I probably have type 2. I do not

have a lot of pain. I do have aching and stiffness. My pain is arthritic from

impaired gait or secondary to muscle strains. I am " sore " but not the severe

pain many describe. However, MANY with type 2 describe severe pain, some with

type 1 do not. It seems to be as individual as many other things relating to

CMT. We- recently had a lot of discussion about pain, pain scales, etc. The

pain of many CMT'ers is very real. On another note, pain thresholds differ.

What one describes as bad may only be slight to others. Many agree that our

pain has a lot to do with secondary symptoms as I described. If they ever

discover why any one type of CMT varies greatly from individual to individual,

even in the same family, they may have a key to helping prevent the damage.

----- Original Message -----

From: jross56922@...

egroups

Sent: Friday, September 01, 2000 2:14 PM

Subject: Re: [] Fw: CMT Type 2/TO JR.

My Groups | Main Page

OK? Do you have severe pain with type 2 as I do with type 1?

September 1, 2000

Lamar son wrote:

>

> JR,

> Lamar here,

>

> I do not have Type 1, HNPP, or X-linked, so I probably have type 2. I do not