Clinical Diagnosis

DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) is a so-called “dominant intermediate form” of CMT neuropathy because it is inherited in an autosomal dominant manner and it is “intermediate” between a demyelinating and axonal neuropathy using strict electrophysiologic criteria for nerve conduction velocities (NCVs). In intermediate CMT median motor NCVs are between 25 and 45 m/s [Davis et al 1978, Nicholson & Myers 2006].

Classic CMT symptoms of sensory and motor deficiencies at the lower legs dominate the clinical picture: sensory deficits, depressed ankle reflex, atrophy, and foot deformities.

The diagnosis can only be established with molecular genetic testing of the DNM2 gene.

Molecular Genetic Testing

Gene. DNM2 is the only gene associated with DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB).

Clinical testing

• Sequence analysis detects a mutation in nearly 100% of individuals with DI-CMTB.

Table 1. Summary of Molecular Genetic Testing Used in DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
DNM2	Sequence analysis	Sequence variants 2	Nearly 100%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband, the identification of a disease-causing mutation in DNM2 is necessary.

• In a person with a CMT phenotype and very slow NCV (<30m/s), perform molecular genetic testing of PMP22 first to determine if a PMP22 duplication, the most common cause of this demyelinating phenotype, is present.

• In a person with a CMT phenotype and intermediate to normal NCV, perform molecular genetic testing of the MPZ, GJB1 (encoding the protein connexin 32), and MFN2 genes first because mutation of one of these genes is a common cause of this phenotype.

• In a person with a CMT phenotype and NCV between 30 and 45 m/s in whom testing for the above genes has not identified a disease-causing mutation, molecular genetic testing of DNM2 is appropriate.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Autosomal dominant centronuclear myopathy (DNM2-related CNM) is also associated with mutations in DNM2 [Bitoun et al 2005]. DNM2-related CNM usually presents with neonatal hypotonia, weak suck, poor feeding and progressive muscle weakness with respiratory problems [Jungbluth et al 2010, Melberg et al 2010].

Some individuals with CNM have clinical findings that overlap with DI-CMTB [Fischer et al 2006, Bitoun et al 2008, Susman et al 2010]. The findings shared between DI-CMTB and CNM are muscle weakness and sometimes cataract. CNM does not have peripheral nerve involvement and often has proximal muscle weakness that is not seen in DI-CMTB.

Natural History

DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) has a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy phenotype that often includes pes cavus foot deformity, depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss.

Mean age at onset is 16 years; onset range is from age two to 50 years. Some persons require AFO braces or other walking aids. Three per cent of affected individuals become wheelchair bound; one person in the Claeys et al [2009] study required a wheelchair at age 61 years.

Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years).

Electrophysiologic studies indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values. Pure axonal CMT has been described.

Sural nerve biopsy has shown diffuse loss of large myelinated fibers, clusters of regenerating myelinated axons, and fibers with focal myelin thickenings [Kennerson et al 2001, Claeys et al 2009].

Genotype-Phenotype Correlations

Strong genotype-phenotype correlations have not been reported.

The majority of DNM2 mutations appear to be in the domain encoding homology to pleckstrin [Züchner et al 2005, Fabrizi et al 2007]; however, exceptions have been identified [Claeys et al 2009, Susman et al 2010].

Penetrance

DNM2 mutations appear to be nearly fully penetrant by young adulthood [Züchner et al 2005].

Anticipation

Anticipation is not observed.

Prevalence

DI-CMTB is a rare cause of CMT. Up to 3.4% of CMT is caused by a DNM2 mutation [Claeys et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB), the following evaluations are recommended:

• Neurologic examination

• Electrophysiologic studies to help differentiate from demyelinating forms of CMT and to establish a baseline for further monitoring of disease progression

• Complete blood count (CBC) with absolute neutrophil count (ANC) to evaluate for neutropenia

• Ophthalmologic examination for cataract

Treatment of Manifestations

Treatment of DI-CMTB is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, orthopedic surgeons, and physical and occupational therapists.

Treatment may include:

• Ankle/foot orthoses

• Orthopedic surgery

• Forearm crutches or canes; wheelchairs

• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs)

• Career and employment counseling

Surveillance

Surveillance includes regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.

Agents/Circumstances to Avoid

Medications which are toxic or potentially toxic to persons with CMT comprise a range of risks including:

• Definite high risk: Vinca alkaloids (vincristine)

  • This category should be avoided by all persons with CMT, including those who are asymptomatic.

• Other potential risk levels: See Table 2. For more information, click here (pdf).

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with DI-CMTB have an affected parent.

• A proband with DI-CMTB may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include DNM2 molecular genetic testing for the mutation identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with DI-CMTB have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected and/or has a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• The sibs of a proband with clinically unaffected parents are still at increased risk for DI-CMTB because of the possibility of reduced penetrance in a parent.

• If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with DI-CMTB has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a disease-causing mutation, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like DI-CMTB) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 8 July 2010 (me) Review posted live

• 26 March 2010 (sz) Original submission