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Charcot-Marie-Tooth
H e r e d i t a r y N e u r o p a t h y O v e r v i e w
Association
By THOMAS D. BIRD, MD
thy genes is done as a grouped panel, whichmay be less expensive than sequential testing of E V A L U A T I O N S T R A T E G Y
each individual gene (if more than two or three 1 - 8 0 0 - 6 0 6 - C M TA
Establishing the specific cause of CMT heredi-tary neuropathy for a given patient involves amedical history, physical examination, neurolog- T E S T I N G S T R A T E G I E S F O R
ic examination, and nerve conduction velocity P A T I E N T S W I T H C M T
(NCV) and EMG testing, as well as a detailedfamily history and the use of DNA-based testing, Positive family history.
In families with at least two-generation involve-ment, known male-to-male transmission, and C L I N I C A L E V A L U A T I O N
slow NCVs, the CMT1A (PMP22 dup) test In individuals who have no family history of should be obtained first, and then, if normal,followed by the CMT1B (MPZ) test.
neuropathy, the first step is to exclude potentialacquired causes of neuropathy by standard neu- In families with at least two-generation involve- rologic evaluation In CMT1, the most common ment and slow NCVs, but without male-to-male variety, NCVs are very slow and peripheral nerves may be palpably enlarged. This is not DNA tests should be done sequentially.
In families with probable X-linked inheritance of F A M I L Y H I S T O R Y
the CMT phenotype, molecular genetic testingof the GJB1 gene (encoding the protein connexin A three-generation family history with attention 32) for CMTX is appropriate in order to confirm to other relatives with neurologic signs and symptoms should be obtained. Documentation In patients with the CMT2 phenotype, molecu- of relevant findings in relatives can be accom- lar genetic testing of MPZ and GJB1 is appropri- plished either through direct examination of ate, given that the CMT2 phenotype can be seen those individuals or review of their medical records, including the results of molecular genet-ic testing and EMG and NCV studies. Patients Negative family history.
with CMT may have a negative family history for many genetic reasons, including mild subclinical all be performed on males and females who expression in other family members, autosomal have no family history of neuropathy, because recessive inheritance, and a new mutation for a new duplications of the 17p11 region often dominant gene. About one third of patients with identifiable mutations causing the CMT1 heredi- female carriers of a GJB1 mutation causing tary neuropathy phenotype have new (de novo) mutations, and thus present as “sporadic” cases.
Testing for rare causes of CMT.
M O L E C U L A R G E N E T I C T E S T I N G
Mutations in EGR2 (CMT1D, CMT4E), NFL(CMT2E), and PDX (CMT4F), and point muta- Molecular genetic testing is clinically available tions in PMP-22 are rare causes of the CMT phe- notype. DNA-based tests are available to identify mutations in these genes. When tests for the genetic testing is available for mutations in sev- more common forms of CMT are negative, the eral different genes associated with remarkable physician must decide if searching for the other, phenotypic overlap, the following strategy may much more rare types of CMT justifies the cost.
provide the most efficient and cost-effective Prognosis and genetic counseling are frequently approach to testing. However, it should be mentioned reasons for such extensive testing.
Excerpted from
noted that in many clinical laboratories, the test- our newsletter:
ing for mutations involving hereditary neuropa- N E G A T I V E M O L E C U L A R G E N E T I C
must be identified before prenatal testing can be T E S T I N G R E S U L T S
Requests for prenatal diagnosis of (typically) Negative DNA testing results do not rule out a Charcot-Marie-Tooth
adult-onset diseases are uncommon. Differences diagnosis of CMT since those normal test results in perspective may exist among medical profes- Association
are compatible with undetected mutations in sionals and within families regarding the use of other genes causing hereditary neuropathy.
prenatal testing, particularly if the testing is being considered for the purpose of pregnancy G E N E T I C C O U N S E L I N G I S S U E S
termination rather than early diagnosis.
Considerations in families with an apparent
Although most centers would consider decisions 1 - 8 0 0 - 6 0 6 - C M TA
de novo (new) mutation. When the parents of a
about prenatal testing to be the choice of the child with an autosomal or X-linked dominant parents, careful discussion of these issues is condition are unaffected, possible non-medical explanations include alternate paternity orundisclosed adoption.
M A N A G E M E N T
Family planning. The optimal time for determi-
No treatment for CMT that reverses or slows the nation of genetic risk, clarification of carrier sta- natural disease process exists. Treatment is tus, and discussion of the availability of prenatal symptomatic and patients are often evaluated testing is before pregnancy. Similarly, decisions and managed by a multi-disciplinary team that about testing to determine the genetic status of includes neurologists, physiatrists, orthopedic at-risk asymptomatic family members are best surgeons, and physical and occupational thera- made before pregnancy. One study found that pists. Daily heel cord stretching exercises to pre- many patients with CMT give themselves high vent Achilles’ tendon shortening are desirable.
disability ratings and 36% would choose not to Special shoes, including those with good ankle support, may be needed. Patients often requireankle/foot orthoses (AFOs) to correct foot drop Testing of asymptomatic adult relatives who
and aid walking. Orthopedic surgery may be are at risk of developing CMT is possible after required to correct severe pes cavus deformity.
direct DNA testing has identified the specific Some patients require forearm crutches or canes gene mutation in an affected relative. Such test- for gait stability, but fewer than 5% of patients ing should be performed in the context of for- need wheelchairs. Obesity is to be avoided because it makes walking more difficult.
Testing of asymptomatic at-risk children is
Exercise is encouraged within the patient’s capa- discouraged. (See also the National Society of
bility and many individuals remain physically Genetic Counselors resolution on genetic testing active. Important career and employment impli- cations exist because of the persistent weaknessof hands and/or feet.
DNA banking. DNA banking is the storage of
Drugs and medications such as vincristine, DNA that has been extracted from white blood paclitaxel, cisplatin, isoniazid, and nitrofurantoin cells for possible future use. Because it is likely that are known to cause nerve damage should that testing methodologies and our understand- ing of genes, mutations, and diseases will The cause of any pain should be identified improve in the future, consideration should be as accurately as possible. Musculoskeletal pain given to banking DNA. DNA banking is particu- may respond to acetaminophen or nonsteroidal larly important in situations in which molecular anti-inflammatory agents. Neuropathic pain may genetic testing is available on a research basis respond to tricyclic antidepressants or drugs only or the sensitivity of currently available test- such as carbamazepine or gabapentin. Initial, but not long-term improvement has been shownin a few patients with CMT1 and sudden deteri- P R E N A T A L T E S T I N G
oration who were treated with steroids (pred- Prenatal diagnosis for pregnancies at increased risk for CMT1A, CMT1B, CMT2E, or CMTX ispossible. DNA extracted from cells obtained bychorionic villus sampling (CVS) at about 10 to * Gestational age is expressed as menstrual 12 weeks’ gestation* or amniocentesis at 16 to weeks calculated either from the first day of 18 weeks’ gestation is analyzed. The disease- the last normal menstrual period or by ultra- causing allele of an affected family member

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