• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

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

Synonym: CMT2E/1F

, MD, PhD and , PhD.

Author Information
, MD, PhD
VIB Department of Molecular Genetics
University of Antwerp
Antwerpen, Belgium
, PhD
VIB Department of Molecular Genetics
University of Antwerp
Antwerpen, Belgium

Initial Posting: ; Last Update: October 27, 2011.

Summary

Disease characteristics. Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is characterized by a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. Disease onset ranges from the first to the fifth decade of life; in some cases disease onset can be in infancy. Affected individuals have difficulty walking and running because of progressive distal weakness and wasting of the muscles 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, hammer toes, and claw hands are frequently observed. Ambulation is generally preserved.

Diagnosis/testing. In most individuals, nerve conduction velocities (NCVs) are severely to moderately reduced and fall within the CMT1 range (i.e., <38 m/sec for the motor median nerve), although near-normal NCVs have been described. NEFL, encoding the protein neurofilament light chain, is the only gene known to be associated with CMT2E/1F.

Management. Treatment of manifestations: Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment may include: special shoes with good ankle support, daily heel cord stretching exercises, ankle/foot orthoses, orthopedic surgery for severe pes cavus deformity, and crutches or canes for stability. Exercise is encouraged. Pain is treated symptomatically.

Prevention of secondary complications: Daily heel cord stretching exercises to prevent Achilles' tendon shortening.

Surveillance: Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.

Agents/circumstances to avoid: Obesity because it makes walking more difficult; drugs and medications (e.g., vincristine, isoniazid, taxol, cisplatin, nitrofurantoin) that are known to cause nerve damage.

Genetic counseling. CMT2E/1F is usually inherited in an autosomal dominant manner; on rare occasion it can be inherited in an autosomal recessive manner.

Autosomal dominant CMT2E/1F: Most individuals with autosomal dominant CMT2E/1F have an affected parent. De novo mutations are more typical for individuals with a severe phenotype. The risk to sibs depends on the genetic status of the proband's parents. Each child of an individual with autosomal dominant CMT2E/1F has a 50% chance of inheriting the mutation.

Autosomal recessive CMT2E/1F: The risk to each sib of an affected individual at conception is 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Prenatal testing for pregnancies at increased risk for both autosomal dominant and autosomal recessive CMT2E/1F is possible if the disease-causing mutation(s) in the family are known.

Diagnosis

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 12 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]. Giant axons with focal accumulation of disorganized neurofilaments are also described [Fabrizi et al 2004, Fabrizi et al 2007]. In an individual with autosomal recessive CMT2E/1F, a markedly reduced number of myelinated axons and only small diameter myelinated axons lacking intermediate filaments are observed [Yum et al 2009].

Molecular Genetic Testing

Gene. NEFL, encoding the protein neurofilament light chain, is the only gene in which mutations are known to cause CMT2E/1F.

Clinical testing

  • Sequence analysis. Pathologic variants identified to date are point mutations, small deletions, insertions, or in/dels in NEFL, all of which are identifiable by sequence analysis.

    To date, deletion or duplication of exons or of the entire gene has not been reported.

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

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
NEFLSequence analysis Sequence variants 2100%

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

Testing Strategy

To confirm/establish the diagnosis in a proband with a progressive peripheral motor and sensory neuropathy requires sequence analysis of the complete NEFL coding sequence.

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

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

Clinical Description

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 five decades of life and presents with a broad clinical phenotype — from an early-onset severe phenotype to milder forms.

Some affected individuals have onset in infancy or early childhood and may display hypotonia and mildly delayed motor milestones. The presenting symptoms in most individuals 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. In the most severely affected people, mild-to-moderate proximal arm and shoulder girdle weakness can be observed.

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.

Cerebellar dysfunction, tremor, and hearing loss are occasionally observed.

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

There are no obvious genotype/phenotype correlations, mainly because of the small number of reported individuals with NEFL mutations. However, Miltenberger-Miltenyi et al [2007] noted that mutations in the head domain of NEFL may cause more severe slowing of nerve conduction velocity than mutations in the coil 2B domain.

Individuals with autosomal recessive CMT2E/1F usually have more a severe phenotype, diagnosed as CMT1F.

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 having CMT2E [Mersiyanova et al 2000], while those with a CMT1 electrophysiologic phenotype are classified as having CMT1F.

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 early infancy or childhood and the course is usually more severe. These individuals 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.

The reported autosomal dominant as well as autosomal recessive mode of inheritance of the disease further complicates the nosologic classification.

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 phenotype and for about 1% of the individuals with neuropathy onset within the first year of life [Baets et al 2011].

Differential Diagnosis

The clinical and electrophysiologic phenotype of CMT2E/CMT1F is undistinguishable from other forms of CMT/DSS (see Charcot-Marie-Tooth Hereditary Neuropathy Overview). In individuals with no family history of CMT, acquired neuropathy should also be considered.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Medical genetics consultation

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 [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.
  • 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 [Gemignani et al 2004].

Prevention of Secondary Complications

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

Surveillance

Monitoring of gait and condition of feet to determine need for bracing, special shoes, surgery is appropriate.

Agents/Circumstances to Avoid

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

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).

Table 2. Medications Potentially Toxic to Persons with CMT

Moderate to Significant Risk 1
- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & Oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava)
- Metronidazole/Misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or Vitamin B12 deficiency)
- Perhexiline (not used in U.S.)
- Pyridoxine (mega dose of Vitamin B6)
- Stavudine (d4T, Zerit)
- Suramin
- Taxols (paclitaxel, docetaxel)
- Thalidomide
- Zalcitabine (ddC, Hivid)

Click here (pdf) for additional medications in lesser-risk categories.

The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.

1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996], Nishikawa et al [2008], and Porter et al [2009]

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation 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.

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. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

To date, two families with autosomal recessive CMT2E/1F (caused by homozygous nonsense mutations) have been reported [Abe et al 2009, Yum et al 2009].

Risk to Family Members−Autosomal Dominant Inheritance

Parents of a proband

Note: Although most individuals diagnosed with autosomal dominant 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 on the genetic status of the proband's parents.
  • If a parent has a disease-causing autosomal dominant 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 leukocyte DNA of either parent, it is most likely caused by a de novo mutation in the proband. Another remote possibility is germline mosaicism, which 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 on the status of the proband's parents. If a parent is affected or known to have a disease-causing mutation, his or her family members are at risk.

Risk to Family Members−Autosomal Recessive Inheritance

Parents of a proband

  • Parents of a proband with CMT1F/CMT2E inherited in an autosomal recessive manner are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of a proband with autosomal recessive CMT1F/CMT2E are obligate heterozygotes (carriers).
  • In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.

Other family members of the proband. Each sib of a proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible once the NEFL mutations have been identified in the family.

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, clarification of carrier status, 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, are carriers, or are at risk.

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.

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 to 18 weeks' gestation. The disease-causing allele(s) 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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association CMT France
    13 allée de Grèce
    35140 Saint Aubin du Cormier
    France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • TREAT-NMD
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 0 191 241 8605
    Fax: 44 0 191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry 91002
    France
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Charcot-Marie-Tooth Neuropathy Type 2E/1F: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 2E/1F (View All in OMIM)

162280NEUROFILAMENT PROTEIN, LIGHT POLYPEPTIDE; NEFL
607684CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E; CMT2E
607734CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1F; CMT1F

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 the 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. NEFL self-assembly is accelerated by binding to phosphatidylinositol phosphates [Kim et al 2011].

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. NEFL is organized in four coding exons. To date, multiple normal and pathogenic sequence variants are reported. See Table 3.

Table 3. Selected NEFL Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
ReferencesReference Sequences
Normalc.-42delT--Yoshihara et al [2002] NM_006158​.3
NP_006149​.2
c.19G>Ap.Glu7LysJordanova et al [2003]
c.123C>T
(120A>T)
p.= 2
(S40S)
Jordanova et al [2003]
c.192G>A
(189G>A)
p.= 2
(L63L)
Jordanova et al [2003]
c.227T>C
(224T>C)
p.Val76Ala
(Val75Ala)
Yoshihara et al [2002]
c.279G>A
(276G>A)
p.= 2
(Q92Q)
Yoshihara et al [2002]
c.423G>A
(420G>A)
p.= 2
(Q140Q)
Jordanova et al [2003]
c.667C>T
(670C>T)
p.= 2
(L224L)
Jordanova et al [2003]
c.720C>T
(723C>T)
p.= 2
(Y241Y)
Jordanova et al [2003]
c.1212C>T
(1215C>T)
p.= 2
(S405S)
Jordanova et al [2003]
c.1326C>T
(1329C>T)
p.= 2
(Y443Y)
Luo et al [2003]
c.1402G>A
(1405G>A)
p.Asp468Asn
(Asp469Asn)
Vechio et al [1996], Jordanova et al [2003]
c.1458C>T
(1461G>T)
p.= 2
(A487A)
Jordanova et al [2003]
c.1492G>A
(1495G>A)
p.Ala498Thr
(Ala499Thr)
Yoshihara et al [2002]
c.1579_1581del
(1582-1584delGAG)
p.Glu527del
(Glu528del)
Yoshihara et al [2002], Yamamoto et al [2004]
c.1573_1574insGAG
(1576-1577insGAG)
p.Glu524_Glu525insGly
(Glu526fs*532)
Andrigo et al [2005]
Pathologicc.[22C>A; 23C>G]p.Pro8ArgDe Jonghe et al [2001]
c.23C>Gp.Pro8ArgJordanova et al [2003]
c.23C>Ap.Pro8GlnJordanova et al [2003]
c.23C>Tp.Pro8LeuJordanova et al [2003]
c.64C>Ap.Pro22ThrYoshihara et al [2002]
c.64C>Tp.Pro22SerGeorgiou et al [2002]
c.268G>A
(265G>A)
p.Glu90Lys
(Glu89Lys)
Jordanova et al [2003]
c.293A>G
(290A>G)
p.Asn98Ser
(Asn97Ser)
Yoshihara et al [2002], Jordanova et al [2003]
c.418G>T 3p.Glu140* Abe et al [2009]
c.446C>T
(443C>T)
p.Ala149Val
(Ala148Val)
Yoshihara et al [2002]
c.628G>T 3p.Glu210* Yum et al [2009]
c.995A>C
(998A>C)
p.Gln332Pro
(Gln333Pro)
Mersiyanova et al [2000]
c.998T>C
(1001T>C)
p.Leu333Pro
(Leu334Pro)
Choi et al [2004]
c.1186G>A
(1189G>A)
p.Glu396Lys
(Glu397Lys)
Choi et al [2004], Zuchner et al [2004]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.= designates that protein has not been analyzed, but no change is expected

3. Mutations that result in autosomal recessive inheritance

Normal gene product. NEFL codes for a structural protein of 543 amino acids that has 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 protein have normal development but reduced axonal caliber and delayed maturation of regenerating myelinated axons after nerve injury. 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.

The effect of dominant NEFL mutations described in individuals with CMT has been investigated 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, Zhai et al 2007]. In transfected cells, dominant NEFL mutants disrupt both neurofilament self-assembly and co-assembly. In transfected neurons, at least some of them cause aberrant axonal transport of neurofilaments, affect the anterograde and retrograde transport of other cell components, and perturb the localization of mitochondria. This leads to progressive degeneration and loss of neuronal viability. In contrast, the recessive p.Glu210* mutation causes loss of NEFL protein. In affected persons homozygous for this mutation, this leads to lack of neurofilaments and progressive axonal loss [Yum et al 2009].

Two transgenic mouse CMT2E models have been generated to date, expressing p.Pro22Ser and p.Glu396Lys mutations respectively [Dequen et al 2010, Shen et al 2011]. Transgenic mice recapitulate the hallmark features of human pathology, including abnormal hindlimb posture, motor performance deficit, and loss of muscle innervation. Importantly, suppression of the mutant NEFLPro22Ser product after disease onset reverses the neurologic phenotype in mice. These experiments indicate that therapeutic approaches aimed at abolishing or neutralizing the mutant NEFL allele could potentially halt disease progression and reverse the associated disabilities [Dequen et al 2010].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Abe A, Numakura C, Saito K, Koide H, Oka N, Honma A, Kishikawa Y, Hayasaka K. Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype. J Hum Genet. 2009;54:94–7. [PubMed: 19158810]
  2. Al-Chalabi A, Andersen PM, Nilsson P, Chioza B, Andersson JL, Russ C, Shaw CE, Powell JF, Leigh PN. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet. 1999;8:157–64. [PubMed: 9931323]
  3. Andrigo C, Boito C, Prandini P, Mostacciuolo ML, Siciliano G, Angelini C, Pegoraro E. A novel out-of-frame mutation in the neurofilament light chain gene (NEFL) does not result in Charcot-Marie-Tooth disease type 2E. Neurogenetics. 2005;6:49–50. [PubMed: 15654615]
  4. Baets J, Deconinck T, De Vriendt E, Zimoń M, Yperzeele L, Van Hoorenbeeck K, Peeters K, Spiegel R, Parman Y, Ceulemans B, Van Bogaert P, Pou-Serradell A, Bernert G, Dinopoulos A, Auer-Grumbach M, Sallinen SL, Fabrizi GM, Pauly F, Van den Bergh P, Bilir B, Battaloglu E, Madrid RE, Kabzińska D, Kochanski A, Topaloglu H, Miller G, Jordanova A, Timmerman V, De Jonghe P. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011;134:2664–76. [PMC free article: PMC3170533] [PubMed: 21840889]
  5. Brownlees J, Ackerley S, Grierson AJ, Jacobsen NJ, Shea K, Anderton BH, Leigh PN, Shaw CE, Miller CC. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum Mol Genet. 2002;11:2837–44. [PubMed: 12393795]
  6. Carpenter DA, Ip W. Neurofilament triplet protein interactions: evidence for the preferred formation of NF-L-containing dimers and a putative function for the end domains. J Cell Sci. 1996;109:2493–8. [PubMed: 8923210]
  7. Choi BO, Lee MS, Shin SH, Hwang JH, Choi KG, Kim WK, Sunwoo IN, Kim NK, Chung KW. Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Hum Mutat. 2004;24:185–6. [PubMed: 15241803]
  8. Cifuentes-Diaz C, Nicole S, Velasco ME, Borra-Cebrian C, Panozzo C, Frugier T, Millet G, Roblot N, Joshi V, Melki J. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. Hum Mol Genet. 2002;11:1439–47. [PubMed: 12023986]
  9. De Jonghe P, Mersivanova I, Nelis E, Del Favero J, Martin JJ, Van Broeckhoven C, Evgrafov O, Timmerman V. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol. 2001;49:245–9. [PubMed: 11220745]
  10. Dequen F, Filali M, Larivière RC, Perrot R, Hisanaga S, Julien JP. Reversal of neuropathy phenotypes in conditional mouse model of Charcot-Marie-Tooth disease type 2E. Hum Mol Genet. 2010;19:2616–29. [PubMed: 20421365]
  11. Dubois M, Strazielle C, Julien JP, Lalonde R. Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation. J Neurosci Res. 2005;80:751–8. [PubMed: 15884021]
  12. Fabrizi GM, Cavallaro T, Angiari C, Bertolasi L, Cabrini I, Ferrarini M, Rizzuto N. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology. 2004;62:1429–31. [PubMed: 15111691]
  13. Fabrizi GM, Cavallaro T, Angiari C, Cabrini I, Taioli F, Malerba G, Bertolasi L, Rizzuto N. Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain. 2007;130:394–403. [PubMed: 17052987]
  14. Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet. 1994;3:1757–61. [PubMed: 7849698]
  15. Flanigan KM, Crawford TO, Griffin JW, Goebel HH, Kohlschutter A, Ranells J, Camfield PR, Ptacek LJ. Localization of the giant axonal neuropathy gene to chromosome 16q24. Ann Neurol. 1998;43:143–8. [PubMed: 9450783]
  16. Friede RL, Samorajski T. Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat Rec. 1970;167:379–87. [PubMed: 5454590]
  17. Gemignani F, Melli G, Alfieri S, Inglese C, Marbini A. Sensory manifestations in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2004;9:7–14. [PubMed: 14871449]
  18. Georgiou DM, Zidar J, Korosec M, Middleton LT, Kyriakides T, Christodoulou K. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family. Neurogenetics. 2002;4:93–6. [PubMed: 12481988]
  19. Goldman JE, Yen SH, Chiu FC, Peress NS. Lewy bodies of Parkinson's disease contain neurofilament antigens. Science. 1983;221:1082–4. [PubMed: 6308771]
  20. Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77:1356–62. [PubMed: 8608515]
  21. Grandis M, Shy ME. Current Therapy for Charcot-Marie-Tooth Disease. Curr Treat Options Neurol. 2005;7:23–31. [PubMed: 15610704]
  22. Guyton GP, Mann RA. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin. 2000;5:317–26. [PubMed: 11232233]
  23. Holmes JR, Hansen ST. Foot and ankle manifestations of Charcot-Marie-Tooth disease. Foot Ankle. 1993;14:476–86. [PubMed: 8253442]
  24. Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler IJ, Mancias P, Papasozomenos SCh, Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain. 2003;126:590–7. [PubMed: 12566280]
  25. Julien JP. A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis. Biochem Cell Biol. 1995;73:593–7. [PubMed: 8714677]
  26. Julien JP. Neurofilament functions in health and disease. Curr Opin Neurobiol. 1999;9:554–60. [PubMed: 10508735]
  27. Kim SK, Kim H, Yang YR, Suh PG, Chang JS. Phosphatidylinositol phosphates directly bind to neurofilament light chain (NF-L) for the regulation of NF-L self assembly. Exp Mol Med. 2011;43:153–60. [PMC free article: PMC3068298] [PubMed: 21339697]
  28. Luo W, Tang B, Zhao G, Li Q, Xiao J, Yang Q, Xia J. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2003;20:169–70. [PubMed: 12673592]
  29. Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, Petrin AN, Evgrafov OV. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet. 2000;67:37–46. [PMC free article: PMC1287099] [PubMed: 10841809]
  30. Miltenberger-Miltenyi G, Janecke AR, Wanschitz JV, Timmerman V, Windpassinger C, Auer-Grumbach M, Löscher WN. Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene. Arch Neurol. 2007;64:966–70. [PubMed: 17620486]
  31. Nishikawa T, Kawakami K, Kumamoto T, Tonooka S, Abe A, Hayasaka K, Okamoto Y, Kawano Y. Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30:519–21. [PubMed: 18797198]
  32. Perez-Olle R, Jones ST, Liem RK. Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. Hum Mol Genet. 2004;13:2207–20. [PubMed: 15282209]
  33. Perez-Olle R, Leung CL, Liem RK. Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation. J Cell Sci. 2002;115:4937–46. [PubMed: 12432080]
  34. Perez-Olle R, Lopez-Toledano MA, Goryunov D, Cabrera-Poch N, Stefanis L, Brown K, Liem RK. Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. J Neurochem. 2005;93:861–74. [PubMed: 15857389]
  35. Porter CC, Carver AE, Albano EA. Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X. Pediatr Blood Cancer. 2009;52:298–300. [PubMed: 18837430]
  36. Previtali SC, Zerega B, Sherman DL, Brophy PJ, Dina G, King RH, Salih MM, Feltri L, Quattrini A, Ravazzolo R, Wrabetz L, Monaco AP, Bolino A. Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve. Hum Mol Genet. 2003;12:1713–23. [PubMed: 12837694]
  37. Sasaki T, Gotow T, Shiozaki M, Sakaue F, Saito T, Julien JP, Uchiyama Y, Hisanaga S. Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants. Hum Mol Genet. 2006;15:943–52. [PubMed: 16452125]
  38. Shen H, Barry DM, Dale JM, Garcia VB, Calcutt NA, Garcia ML. Muscle pathology without severe nerve pathology in a new mouse model of Charcot-Marie-Tooth disease type 2E. Hum Mol Genet. 2011;20:2535–48. [PMC free article: PMC3109999] [PubMed: 21493625]
  39. Shepherd CE, McCann H, Thiel E, Halliday GM. Neurofilament-immunoreactive neurons in Alzheimer's disease and dementia with Lewy bodies. Neurobiol Dis. 2002;9:249–57. [PubMed: 11895376]
  40. Tokutake S. On the assembly mechanism of neurofilaments. Int J Biochem. 1990;22:1–6. [PubMed: 2184054]
  41. Tomkins J, Usher P, Slade JY, Ince PG, Curtis A, Bushby K, Shaw PJ. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport. 1998;9:3967–70. [PubMed: 9875737]
  42. Vechio JD, Bruijn LI, Xu Z, Brown RH, Cleveland DW. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Ann Neurol. 1996;40:603–10. [PubMed: 8871580]
  43. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci. 2006;242:47–54. [PubMed: 16386273]
  44. Yamamoto M, Yoshihara T, Hattori N, Sobue G. Glu528del in NEFL is a polymorphic variant rather than a disease-causing mutation for Charcot-Marie-Tooth disease in Japan. Neurogenetics. 2004;5:75–7. [PubMed: 14586770]
  45. Yoshihara T, Yamamoto M, Hattori N, Misu K, Mori K, Koike H, Sobue G. Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals. J Peripher Nerv Syst. 2002;7:221–4. [PubMed: 12477167]
  46. Yum SW, Zhang J, Mo K, Li J, Scherer SS. A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy. Ann Neurol. 2009;66:759–70. [PubMed: 20039262]
  47. Zhai J, Lin H, Julien JP, Schlaepfer WW. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. Hum Mol Genet. 2007;16:3103–16. [PubMed: 17881652]
  48. Zuchner S, Vorgerd M, Sindern E, Schroder JM. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord. 2004;14:147–57. [PubMed: 14733962]

Suggested Reading

  1. Carter GT. Rehabilitation management in neuromuscular disease. J Neurol Rehab. 1997;11:69–80.
  2. Chaudhry V, Chaudhry M, Crawford TO, Simmons-O'Brien E, Griffin JW. Toxic neuropathy in patients with pre-existing neuropathy. Neurology. 2003;60:337–40. [PubMed: 12552058]
  3. Lee MK, Marszalek JR, Cleveland DW. A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron. 1994;13:975–88. [PubMed: 7946341]
  4. Nelis E, Haites N, Van Broeckhoven C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat. 1999;13:11–28. [PubMed: 9888385]
  5. Ohara O, Gahara Y, Miyake T, Teraoka H, Kitamura T. Neurofilament deficiency in quail caused by nonsense mutation in neurofilament-L gene. J Cell Biol. 1993;121:387–95. [PMC free article: PMC2200107] [PubMed: 8468353]
  6. Xu Z, Cork LC, Griffin JW, Cleveland DW. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell. 1993;73:23–33. [PubMed: 8462100]
  7. Yamasaki H, Bennett GS, Itakura C, Mizutani M. Defective expression of neurofilament protein subunits in hereditary hypotrophic axonopathy of quail. Lab Invest. 1992;66:734–43. [PubMed: 1602743]
  8. Zhu Q, Couillard-Despres S, Julien JP. Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol. 1997;148:299–316. [PubMed: 9398473]

Chapter Notes

Revision History

  • 27 October 2011 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1187PMID: 20301366
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...