Charcot-Marie-Tooth Neuropathy Type 2E/1F

[CMT2E/1F]

Clinical Diagnosis

Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is suspected in individuals with a progressive peripheral motor and sensory neuropathy.

• Nerve conduction velocities (NCVs) vary widely. In most individuals, NCVs are severely-to-moderately reduced and fall within the CMT1 range, i.e., less than 38 m/sec for the motor median nerve, although near-normal NCVs have also been described. The lowest reported NCV in an individual with CMT2E/1F is 13 m/sec. The amplitudes of the compound action potentials are usually severely reduced. Sensory nerve action potentials are often unrecordable.

• Electromyogram (EMG). Concentric needle EMG shows chronic neurogenic alterations.

• Peripheral nerve biopsy is not obligatory for diagnosis. Histopathologic studies of sural nerve biopsies showed a mixed (demyelinating and axonal) pathology, characterized by reduction mainly of large nerve fibers, thinly myelinated axons, axonal regeneration clusters, and onion bulb formation [Jordanova et al 2003, Zuchner et al 2004]. Another report found giant axons with accumulation of disorganized neurofilaments [Fabrizi et al 2004].

Molecular Genetic Testing

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.—ED.

Gene. NEFL, the gene encoding the protein neurofilament light chain, is the only gene known to be associated with CMT2E/1F.

Clinical uses

• Diagnosis

• Predictive testing

• Prenatal diagnosis

• Preimplantation genetic diagnosis

Clinical testing

• Sequence analysis. Only point mutations in the NEFL gene have been identified so far. All point mutations are identified by sequencing.
  Of note, Jordanova et al [2003] reported an individual with two NEFL mutations c.23C>G/c.19G>A (P8R/E7K). The individual transmitted the P8R mutation to her three affected children. Although functional studies provided evidence that E7K is a normal polymorphic variant [Perez-Olle et al 2004, Yamamoto et al 2004], this finding illustrates that some individuals can have two different NEFL mutations either in trans configuration or cis configuration. Molecular genetic testing should therefore include the complete coding sequence of the NEFL gene, especially in families seeking prenatal diagnosis.
  No large NEFL rearrangements have been reported.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 2E/1F

Test Method	Mutations Detected	Mutation Detection Frequency	Test Availability
Sequence analysis	All reported NEFL mutations	100%	Clinical

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

Genetically Related (Allelic) Disorders

CMT2E/1F is the only disorder associated with mutations in NEFL.

Natural History

CMT2E/1F is a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. The disease onset is within the first three decades of life and presents with a broad clinical phenotype — from an early onset and severe phenotype to milder forms.

Some affected individuals have onset within the first decade of life. The presenting symptoms are difficulties in walking and running as a result of progressive distal weakness and wasting of the lower limbs. Paresis in the distal part of the lower limbs varies from mild weakness to a complete paralysis of the distal muscle groups.

Tendon reflexes are diminished or absent.

Sensory signs are not prominent but are present in all affected individuals.

Pes cavus is the most frequently observed limb deformity, together with hammer toes and claw hands.

Tremor is reported in some individuals. Deafness was observed in one affected individual.

Ambulation is generally preserved during life. Only one individual is reported to be wheelchair bound.

Affected individuals do not have palpably enlarged nerves, ulcerated feet, or paralysis of the vocal cords and/or diaphragm.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are difficult to make because of the small number of reported individuals with NEFL mutations.

Penetrance

Penetrance is most likely to be complete.

Anticipation

No clear evidence of anticipation is available in the literature.

Nomenclature

In the first reported family, NCVs were within the CMT2 range; thus this CMT variant was initially described as CMT2E [Mersiyanova et al 2000]. The subsequent observation of slow NCVs in individuals belonging to similar families and in simplex cases (i.e., those with no family history of the disorder) created a nosologic problem. OMIM classifies individuals with a CMT2 electrophysiologic phenotype as CMT2E [Mersiyanova et al 2000], while those with a CMT1 electrophysiologic phenotype are classified as CMT1F. Thus, CMT1F is characterized by slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, hollow feet, and reduced nerve conduction velocities (<38 m per sec). Onset is in infancy or childhood and the course is usually more severe.

It is still unclear whether the slowing of NCVs is progressive, with young individuals having normal or near-normal NCVs that decline with age and disease progression. If this turns out to be the case, it makes the distinction between CMT2E and CMT1F to a large extent artificial.

Individuals with onset of CMT in the first decade are often diagnosed as having Dejerine-Sottas syndrome (DSS), a term that refers to this phenotype and can be observed in individuals with mutations in a number of genes; thus, the term DSS has become more confusing than helpful when considering the nosology of CMT.

Prevalence

The true prevalence of CMT2E/1F is not known. Preliminary data indicate that NEFL mutations account for 2%-5% of individuals presenting with a CMT or DSS phenotype.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F), the following evaluations are recommended:

• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss

• NCV to help distinguish demyelinating, axonal, and mixed neuropathies

• Complete family history

Treatment of Manifestations

Treatment is symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 1995, Carter 1997, Grandis & Shy 2005].

• Special shoes, including those with good ankle support, may be needed.

• Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.

• Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking [Carter et al 1995, Carter 1997].

• Orthopedic surgery may be required to correct severe pes cavus deformity [Holmes & Hansen 1993, Guyton & Mann 2000].

• Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.

• Exercise is encouraged within the individual's capability and many individuals remain physically active.

• Career and employment choices may be influenced by persistent weakness of hands and/or feet.

• Pain should be treated symptomatically [Carter et al 1998, Gemignani et al 2004].

Prevention of Secondary Complications

Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.

Agents/Circumstances to Avoid

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

Drugs and medications that are known to cause nerve damage (e.g., vincristine, isoniazid, taxol, cisplatin, nitrofurantoin) should be avoided [Graf et al 1996, Chaudhry et al 2003, Weimer & Podwall 2006].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics are a source of 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.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 2E/1F is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals with CMT2E/1F have an affected parent.

• Occasionally, family history may be negative because the proband has a de novo mutation. Individuals with a severe phenotype typically have a de novo mutation.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic and electrophysiologic examination and, if the mutation in the proband has been identified, molecular genetic testing.

Note: Although most individuals diagnosed with CMT2E/1F 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.

Sibs of a proband

• The risk to sibs depends upon the genetic status of the proband's parents.

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

• The presence of a NEFL mutation in a sib does not predict the severity of symptoms, the age of onset, or the progression of the disorder.

• If the disease-causing mutation identified in the proband cannot be detected in the DNA of either parent, it is most likely caused by a de novo mutation in the proband. Another remote possibility is germline mosaicism, but this has not been reported to date.

Offspring of a proband

• Each child of an individual with CMT2E/1F has a 50% chance of inheriting the mutation.

• The presence of a NEFL mutation in the offspring does not predict the severity of symptoms, the age of onset, or the progression of the disorder.

• Individuals who are severely affected may not reproduce.

Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is affected or to have a disease-causing mutation, his or her family members are 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 the disease-causing mutation or clinical evidence of the disorder, 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.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. 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 chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

The cytoskeleton of neuronal cells is mainly composed of three kinds of filaments: microtubules, neurofilaments, and actin filaments [Tokutake 1990]. Neurofilaments (NFs) belong to the family of intermediate filaments (IF) and are the most abundant component of the mature myelinated axon [Friede & Samorajski 1970]. They have a central 310-amino acid domain (rod-domain) shaped as a large coiled-coil α-helix flanked by two non-helical segments: the N-terminal head and C-terminal tail. Neurofilaments self-assemble into heteropolymers; this assembly is mediated by interactions among the rod domains of each subunit, whereas the specificity of the interactions is determined by the end domains [Carpenter & Ip 1996].

Neurofilaments in vertebrates are composed of three different protein subunits, referred to as neurofilament light chain (NEFL, 68 kd), neurofilament medium chain (NEFM, 160 kd), and neurofilament heavy chain (NEFH, 210 kd), each of these encoded by different genes [Julien 1999]. NEFL is the most abundant unit of neurofilaments and plays a central role in their assembly. It is the only NF subunit capable of self-assembling into filaments in vitro [Carpenter & Ip 1996] and also able to regulate the assembly of the other NF subunits.

Disruption of axonal transport of NFs resulting in neurofilament accumulations is a major pathologic hallmark during the early stages of many human motor neuron diseases, including giant axonal neuronopathy [Flanigan et al 1998], amyotrophic lateral sclerosis [Julien 1995], Parkinson disease [Goldman et al 1983], Lewy-body-type dementia [Shepherd et al 2002], Alzheimer disease [Figlewicz et al 1994, Tomkins et al 1998, Al-Chalabi et al 1999], and spinal muscular atrophy [Cifuentes-Diaz et al 2002].

Normal allelic variants. The NEFL gene is organized in four coding exons. To date, 17 normal sequence variants are reported. See Table 2.

Pathologic allelic variants. The first disease-causing NEFL mutation was reported by Mersiyanova et al [2000]. All currently known NEFL mutations are listed in the Mutation Database of Inherited Peripheral Neuropathies [Nelis et al 1999]. See Table 3.

Normal gene product. The NEFL gene codes for a structural protein of 544 amino acids, with head, rod, and tail domains. NEFL is a structural protein, exclusively and abundantly expressed in neurons and localized principally in axons, with higher levels in large myelinated axons. It assembles with neurofilaments of higher molecular mass, medium (NEFM) and heavy (NEFH), into intermediate filaments type IV, and forms the cytoskeleton of the neuronal cell. NEFL interacts in peripheral nerve with myotubularin-related 2 protein phosphatase (MTMR2), another CMT associated protein mutated in CMT4B1 [Previtali et al 2003]. Neurofilaments are involved in radial growth and caliber maintenance of large myelinated axons and thereby play a role in their conduction velocity.

Abnormal gene product. In the absence of NEFL, NEFM and NEFH subunits are unable to assemble into 10-nm filaments. As a result, mice lacking NEFL have normal development but reduced axonal caliber and delayed maturation of regenerating myelinated axons after nerve injury [Zhu et al 1997]. They develop mild sensorimotor dysfunction and spatial deficit without overt signs of paresis [Dubois et al 2005]. In Japanese quail natural mutants lacking NEFL, the normal radial growth of myelinated axons is severely attenuated [Yamasaki et al 1992, Ohara et al 1993]. The more severe CMT-like phenotypes resemble mice with NEFL overexpression or knock-in mutant mice (L394P). They have massive selective degeneration of spinal motor neurons, accompanied by abnormal accumulations of NFs and severe neurogenic atrophy of skeletal muscles [Xu et al 1993, Lee et al 1994].

To date, three groups have investigated the effect of NEFL mutations, described in individuals with CMT, in transgenic mammalian cells and neurons [Brownlees et al 2002, Perez-Olle et al 2002, Perez-Olle et al 2004, Perez-Olle et al 2005, Sasaki et al 2006]. CMT mutant neurofilaments disrupt both neurofilament self-assembly and co-assembly. They have aberrant axonal transport, affect the anterograde and retrograde transport of other cell components,and perturb the localization of mitochondria in neurons. Overexpression of mutant proteins results in neuritic degeneration.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 15 June 2006 (ca) Comprehensive update posted to live Web site

• 1 April 2004 (me) Review posted to live Web site

• 6 October 2003 (pdj) Original submission