DiagnosisClinical DiagnosisCharcot-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 TestingGene. 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/1FView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityNEFLSequence analysis Sequence variants 2100%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test resultsBecause of the presence of recessive mutations, as well as normal variants in the coding region (see Table 3 for examples), segregation of the mutations should be traced in the family (when possible) and normal controls should be tested. For example, Jordanova et al [2003] reported an individual with two NEFL variants p.Pro8Arg and p.Glu7Lys. Further studies demonstrated that these variants were in trans configuration and p.Pro8Arg was transmitted to the affected children while p.Glu7Lys was a normal variant [Perez-Olle et al 2004, Yamamoto et al 2004].For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).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.Genetically Related (Allelic) DisordersCMT2E/1F is the only disorder associated with mutations in NEFL.}

Natural HistoryCMT2E/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 CorrelationsThere 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.

Differential DiagnosisThe 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations 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 consultationTreatment of ManifestationsTreatment 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 ComplicationsDaily 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 AvoidObesity 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 CMTView in own windowModerate to Significant Risk <sup>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 InvestigationSearch 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.</sup>

Molecular GeneticsInformation 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 DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCMT2ENEFL8p21​.2Neurofilament light polypeptideHuman Intermediate Filament Database NEFL
IPN Mutations, NEFL
NEFL homepage - Leiden Muscular Dystrophy pagesNEFLData 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) View in own window 162280NEUROFILAMENT PROTEIN, LIGHT POLYPEPTIDE; NEFL 607684CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E; CMT2E 607734CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1F; CMT1FMolecular Genetic PathogenesisThe 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 View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change
(Alias ¹)ReferencesReference SequencesNormalc.-42delT--Yoshihara et al [2002] NM_006158​.3
NP_006149​.2c.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] See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. p.= designates that protein has not been analyzed, but no change is expected3. Mutations that result in autosomal recessive inheritanceNormal 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].}