Re: Genetics - more

[Guest guest]

More notes about the genetics of CMT - the syndrome.

http://www.geneclinics.org/

Disease characteristics. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy

refers to a group of disorders that are genetic and produce a chronic motor

and sensory polyneuropathy. The typical patient has distal muscle weakness

and atrophy often associated with mild to moderate sensory loss, depressed

tendon reflexes, and high-arched feet.

Diagnosis/testing. The genetic neuropathies need to be carefully

distinguished from the many causes of acquired (non-genetic) neuropathies.

Clinical diagnosis is based on family history and characteristic findings on

physical examination, EMG/NCV testing, and occasionally on sural nerve

biopsy. DNA-based clinical/commercial testing is available for three types of

CMT: CMT1A (17p11 duplication), HNPP (17p11 deletion), and CMTX (connexin

32).

Genetic counseling. The CMT syndrome can be inherited in an autosomal

dominant, autosomal recessive, or X-linked manner. Genetic counseling and

risk assessment depend on a careful determination of the specific CMT subtype.

----------

Diagnosis

Establishing the correct diagnosis for a given patient involves a medical

history, physical examination, and neurologic examination, as well as a

detailed family history and the use of DNA-based testing.

Family history. A three-generation family history with attention to other

relatives with neurologic signs and symptoms should be obtained.

Documentation of relevant findings in relatives can be accomplished either

through direct examination of those individuals or review of their medical

records, including the results of DNA-based testing and EMG studies. Patients

with CMT may have a negative family history for many reasons, including mild

subclinical expression in other family members, recessive inheritance, a new

mutation for a dominant gene, and false paternity.

Clinical findings. Painless, symmetric, slowly progressive motor neuropathy

of the arms and legs beginning in the 1st-3rd decade with a positive family

history suggests CMT. The acute onset of painless, focal sensory/motor

neuropathy in a single nerve with a history of other affected family members

suggests HNPP. Sudden onset of pain and weakness in the shoulder or upper arm

associated with distal and/or proximal weakness and atrophy of the upper

extremity with other similarly affected family members suggests Familial

Brachial Plexus Neuropathy. Typical CMT patients have high-arched feet, weak

ankle dorsiflexion, thin distal muscles, depressed tendon reflexes, and

distal sensory loss. In CMT1, the most common variety, NCV's are very slow

and peripheral nerves may be palpably enlarged.

DNA-based testing. DNA-based tests are presently clinically available for

CMT1A, CMTX, and HNPP. DNA-based testing to assess the number of PMP-22 genes

detects >95% of patients with CMT1A (who have 3 copies of the gene) and ~100%

of patients with HNPP (who have 1 copy of the gene). Patients with CMTX have

identifiable mutations in the connexin 32 gene.

Test strategies for patients with CMT. In families with at least

two-generation involvement, known male-to-male transmission, and slow NCV,

the CMT1A test should be obtained. In families with at least two-generation

involvement but without male-to-male transmission, the CMT1A and CMTX DNA

tests should be done sequentially. In families with apparent X-linked

inheritance of the CMT phenotype, mutation analysis of the connexin 32 gene

is appropriate in order to confirm the diagnosis.

In sporadic cases, the first step is to exclude potential acquired causes of

neuropathy by standard neurological evaluation. Both CMT1A and CMTX DNA tests

should be performed on males and females who are sporadic cases, because new

duplications of the 17p11 region often occur and because female carriers of a

connexin 32 disease-causing mutation may be symptomatic.

Negative DNA testing results for the PMP-22 gene and connexin 32 gene cannot

correctly rule out a diagnosis of CMT since those test results may be

compatible with an undetected point mutation in PMP-22, CMT1B, CMT1C, CMT2,

or some other form of hereditary neuropathy.

The HNPP DNA test in which a deletion of the PMP-22 gene is present (such

that affected individuals have only one copy of the gene) is also clinically

available and should be obtained in individuals with recurrent pressure

palsies.

[Guest guest]

More notes about the genetics of CMT - the syndrome.

http://www.geneclinics.org/

Disease characteristics. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy

refers to a group of disorders that are genetic and produce a chronic motor

and sensory polyneuropathy. The typical patient has distal muscle weakness

and atrophy often associated with mild to moderate sensory loss, depressed

tendon reflexes, and high-arched feet.

Diagnosis/testing. The genetic neuropathies need to be carefully

distinguished from the many causes of acquired (non-genetic) neuropathies.

Clinical diagnosis is based on family history and characteristic findings on

physical examination, EMG/NCV testing, and occasionally on sural nerve

biopsy. DNA-based clinical/commercial testing is available for three types of

CMT: CMT1A (17p11 duplication), HNPP (17p11 deletion), and CMTX (connexin

32).

Genetic counseling. The CMT syndrome can be inherited in an autosomal

dominant, autosomal recessive, or X-linked manner. Genetic counseling and

risk assessment depend on a careful determination of the specific CMT subtype.

----------

Diagnosis

Establishing the correct diagnosis for a given patient involves a medical

history, physical examination, and neurologic examination, as well as a

detailed family history and the use of DNA-based testing.

Family history. A three-generation family history with attention to other

relatives with neurologic signs and symptoms should be obtained.

Documentation of relevant findings in relatives can be accomplished either

through direct examination of those individuals or review of their medical

records, including the results of DNA-based testing and EMG studies. Patients

with CMT may have a negative family history for many reasons, including mild

subclinical expression in other family members, recessive inheritance, a new

mutation for a dominant gene, and false paternity.

Clinical findings. Painless, symmetric, slowly progressive motor neuropathy

of the arms and legs beginning in the 1st-3rd decade with a positive family

history suggests CMT. The acute onset of painless, focal sensory/motor

neuropathy in a single nerve with a history of other affected family members

suggests HNPP. Sudden onset of pain and weakness in the shoulder or upper arm

associated with distal and/or proximal weakness and atrophy of the upper

extremity with other similarly affected family members suggests Familial

Brachial Plexus Neuropathy. Typical CMT patients have high-arched feet, weak

ankle dorsiflexion, thin distal muscles, depressed tendon reflexes, and

distal sensory loss. In CMT1, the most common variety, NCV's are very slow

and peripheral nerves may be palpably enlarged.

DNA-based testing. DNA-based tests are presently clinically available for

CMT1A, CMTX, and HNPP. DNA-based testing to assess the number of PMP-22 genes

detects >95% of patients with CMT1A (who have 3 copies of the gene) and ~100%

of patients with HNPP (who have 1 copy of the gene). Patients with CMTX have

identifiable mutations in the connexin 32 gene.

Test strategies for patients with CMT. In families with at least

two-generation involvement, known male-to-male transmission, and slow NCV,

the CMT1A test should be obtained. In families with at least two-generation

involvement but without male-to-male transmission, the CMT1A and CMTX DNA

tests should be done sequentially. In families with apparent X-linked

inheritance of the CMT phenotype, mutation analysis of the connexin 32 gene

is appropriate in order to confirm the diagnosis.

In sporadic cases, the first step is to exclude potential acquired causes of

neuropathy by standard neurological evaluation. Both CMT1A and CMTX DNA tests

should be performed on males and females who are sporadic cases, because new

duplications of the 17p11 region often occur and because female carriers of a

connexin 32 disease-causing mutation may be symptomatic.

Negative DNA testing results for the PMP-22 gene and connexin 32 gene cannot

correctly rule out a diagnosis of CMT since those test results may be

compatible with an undetected point mutation in PMP-22, CMT1B, CMT1C, CMT2,

or some other form of hereditary neuropathy.

The HNPP DNA test in which a deletion of the PMP-22 gene is present (such

that affected individuals have only one copy of the gene) is also clinically

available and should be obtained in individuals with recurrent pressure

palsies.

[Guest guest]

<< it just hits a raw nerve every time I read anything regarding CMT that

states (PAINLESS) >>

Thanks for pointing that out. We can't be reminded too often that half of

CMTers do suffer from significant pain. I am one who has the pain, also.

I will edit that out on my master and put in ... instead.

Kat