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MFN2 Hereditary Motor and Sensory Neuropathy

Synonyms: MFN2 Charcot-Marie-Tooth Neuropathy, MFN2-HMSN

, MD, PhD.

Author Information

Initial Posting: ; Last Update: May 14, 2020.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.

Diagnosis/testing.

Molecular genetic testing establishes the diagnosis of MFN2-HMSN in 90% of probands with suggestive findings by identifying a heterozygous MFN2 pathogenic variant and in 10% of probands with suggestive findings by identifying biallelic MFN2 pathogenic variants.

Management.

Treatment of manifestations: Neuropathy is often managed by a multidisciplinary team that includes a neurologist, a physiatrist, an orthopedic surgeon, and physical and occupational therapists. Symptomatic treatment relies on special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain; treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin. Optic atrophy is managed with low vision aids as per a low vision clinic, consultation with community vision services, and career/employment counseling.

Surveillance: Routine evaluation by: a neurologist to assess disease progression; physical therapy to assess gross motor skills including gait and strength; occupational therapy to assess fine motor skills and coping strategies; and ophthalmologist and low vision clinic to assess visual acuity and need for modification of low vision aids, respectively.

Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage; alcohol and malnutrition (which can cause or exacerbate neuropathy).

Genetic counseling.

Approximately 90% of MFN2-HMSN is inherited an autosomal dominant (AD) manner, and approximately 10% is inherited in an autosomal recessive (AR) manner. Semi-dominant inheritance (i.e., an MFN2 pathogenic variant is associated with mild disease in the heterozygous state and more severe disease in the homozygous or compound heterozygous state) has been reported in two families.

  • AD MFN2-HMSN. Most affected individuals have an affected parent; the proportion of individuals with a de novo MFN2 pathogenic variant is unknown. Each child of an affected individual has a 50% chance of inheriting the MFN2 pathogenic variant.
  • AR MFN2-HMSN. At conception, each sib of an individual with autosomal recessive MFN2-HMSN has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (i.e., carrier), and a 25% chance of being unaffected and not a carrier.

Once the MFN2 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MFN2-HMSN are possible.

Diagnosis

Formal diagnostic criteria for MFN2 hereditary motor and sensory neuropathy have not been established.

Suggestive Findings

MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) should be considered in individuals with the following clinical and neurophysiologic findings. Note: No specific findings distinguish MFN2-HMSN from other inherited hereditary motor and sensory neuropathies.

Clinical findings

  • Onset before age ten years (although a wide range has been reported)
  • Involvement of the lower extremities earlier and more severely than the upper extremities
  • Involvement of the distal upper extremities as the neuropathy progresses
  • Motor deficits more prominent than sensory deficits
  • Optic atrophy (~7% in the autosomal dominant form, and ~20% in the autosomal recessive form)

Neurophysiologic findings

  • Nerve conduction velocities (NCVs) are normal (>42 m/s) or only slightly decreased [Saito et al 1997, Züchner et al 2004].
  • Electromyogram (EMG) reveals signs of chronic denervation.

Establishing the Diagnosis

The diagnosis of MFN2-HMSN is established in a proband who has one of the following on molecular genetic testing (see Table 1):

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) (see Option 1) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) (see Option 2) depending on the phenotype.

Option 1

A peripheral neuropathy or axonal neuropathy multigene panel that includes MFN2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of MFN2-HMSN is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in MFN2 Hereditary Motor and Sensory Neuropathy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
MFN2Sequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 5<1% 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

One in 360 individuals with MFN2-HMSN had a deletion of exons 7 and 8 [Polke et al 2011].

Clinical Characteristics

Clinical Description

MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy characterized by earlier and more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, and more prominent motor deficits than sensory deficits.

MFN2-HMSN can be caused by a heterozygous pathogenic variant (autosomal dominant inheritance) or biallelic pathogenic variants (semi-dominant inheritance or autosomal recessive inheritance). The phenotypes associated with the different modes of inheritance do not differ significantly [Pipis et al, in preparation].

Autosomal Dominant MFN2-HMSN

The age at onset and disease progression of MFN2-HMSN vary within and among families; onset ranges from age one year to the sixth decade. Most individuals develop manifestations in the first and second decade. The initial finding is often foot drop or foot weakness. Pes cavus foot deformity may occur.

Motor signs (weakness and atrophy) predominate, but mild sensory loss in the feet is common. Tendon reflexes are usually absent, but occasionally intact or increased. Mild pyramidal signs including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but without spastic gait have been observed [Vucic et al 2003, Zhu et al 2005].

Some individuals with MFN2 pathogenic variants are asymptomatic and have only mild findings on examination; however, the phenotype in those individuals could eventually convert to late-onset MFN2-HMSN [Lawson et al 2005, Dankwa et al 2019, Lin et al 2019].

Postural tremor is common [Muglia et al 2001, Bissar-Tadmouri et al 2004].

Affected individuals with early onset (age <10 years) tend to have more severe disability than those with later onset [Chung et al 2006; Pipis et al, in preparation]. Those with early onset may show optic atrophy, hoarse voice, and proximal weakness.

Subacute onset of optic atrophy with subsequent slow recovery in 60% of individuals with early onset has been reported [Chung et al 2006, Verhoeven et al 2006, Züchner et al 2006]. The majority of reported instances of optic atrophy associated with MFN2-HMSN resulted from de novo MFN2 pathogenic variants.

To date, a single individual with early-onset stroke has been reported [Chung et al 2008].

MFN2-HMSN is progressive. Nearly 27% of individuals become dependent on a wheelchair [Muglia et al 2001; Pipis et al, in preparation]. Life span is usually not reduced.

Semi-Dominant and Autosomal Recessive MFN2-HMSN

Approximately 10% of families have biallelic compound heterozygous variants in MFN2. Most of these have been reported in individuals who showed early onset of disease [Polke et al 2011; Pipis et al, in preparation]. However, Hikiami et al [2018] reported an adult-onset mild phenotype in sisters with homozygous MFN2 variants.

All MFN2-HMSN

Neuroimaging. Periventricular, subcortical, and cerebellar peduncular white matter lesions on brain MRI have been reported in a few individuals [Chung et al 2006, Züchner et al 2006, Klein et al 2011, Oh et al 2014].

Neuropathology. Neuropathologic findings include loss of myelinated nerve fibers (especially large fibers), mitochondrial abnormalities, and (rarely) onion bulb formation [Saito et al 1997, Muglia et al 2001, Verhoeven et al 2006].

Genotype-Phenotype Correlations

Autosomal dominant MFN2-HMSN. Variants in certain amino acid residues are always pathogenic, with no evidence of reduced penetrance or variable expressivity (range of phenotypic expression) despite different amino acid substitutions. Examples of different missense changes observed at the same conserved amino acid residue include p.Arg94Trp/Gln, p.Arg104Glu/Trp, p.Ser249Thr/Cys, p.Trp740Ser/Arg [Pipis et al, in preparation].

In contrast, variants in other amino acid residues are associated with variable expressivity (early vs later onset of disease) dependent on the amino acid substitution at the same residue.

Autosomal dominant vs autosomal recessive variants. No significant genotype-phenotype correlations can be made.

Penetrance

The penetrance for AD MFN2-HMSN is considered to be complete. While some individuals with a heterozygous MFN2 pathogenic variant are asymptomatic and have only mild findings on examination at the time of diagnosis, the disease may prove to be late onset in these instances [Lawson et al 2005].

Nomenclature

Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."

Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene, MFN2-HMSN has been referred to in the past by multiple designations (see Table 2).

Table 2.

Clinical Designations Used to Refer to MFN2 Hereditary Motor and Sensory Neuropathy

DesignationMOIClinical Findings
CMT2A 1AD
AR
Axonal peripheral sensorimotor neuropathy
HMSN VADAxonal peripheral sensorimotor neuropathy w/brisk reflexes
CMT6
CMT6A
HMSN VI
ADOptic atrophy assoc w/MFN2-HMSN phenotype
HMSN VIIADAxonal CMT phenotype w/mild pyramidal signs incl extensor plantar responses, mild ↑ in tone, & preserved or ↑ reflexes, but no spastic gait 2

AD = autosomal dominant; AR = autosomal recessive; HMSN = hereditary motor and sensory neuropathy; MOI = mode of inheritance

1.

Older classification systems may further divide this designation into CMT2A2A (to refer to AD inheritance) and CMT2A2B (to refer to AR inheritance).

2.

Classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g., MFN2) are associated with more than one mode of inheritance (i.e., both autosomal dominant and autosomal recessive) and a range of clinical features (i.e., a pure MFN2-HMSN phenotype and MFN2-HMSN with optic atrophy).

To disambiguate, the general term MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is used in this GeneReview. For further review of nomenclature, see the Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Prevalence

The proportion of CMT caused by pathogenic variants in MFN2 varies by study:

  • Züchner et al [2004] reported seven MFN2 pathogenic variants in 36 families with CMT2, indicating that 19.5% of CMT2 could be caused by MFN2 pathogenic variants.
  • Chung et al [2006] reported that 24% of 62 families with CMT2 in South Korea had pathogenic variants in MFN2.
  • Verhoeven et al [2006] reported that 33% of families with CMT2 in a European/USA study had pathogenic variants in MFN2.
  • Engelfried et al [2006] reported that 8% (6/73) of persons with CMT2, including simplex cases (i.e., a single occurrence in a family), had MFN2 pathogenic variants.
  • Feely et al [2011] reported that MFN2-HMSN accounted for 91% of severely impaired individuals with CMT2 but only 11% of mildly or moderately impaired people.
  • Subsequent publications confirm the frequencies in these early reports both in families/populations largely of Western European ancestry (i.e., in Italy [Gentile et al 2020] and Hungary [Milley et al 2018]), as well as in other populations (i.e., Han Chinese [Sun et al 2017], Han Chinese in Taiwan [Hsu et al 2019], and Japanese [Ando et al 2017]).

Differential Diagnosis

All hereditary motor and sensory neuropathy (HMSN) forms in which axonal phenotypes have been reported, including PMP22-HMSN, MPZ-HMSN, and GJB1-HMSN (see GJB1 Disorders) need to be considered in the differential diagnosis of MFN2-HMSN. See Charcot-Marie-Tooth Hereditary Neuropathy Overview.

MFN2 pathogenic variants are by far the most common cause of autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2). As many as one third of all individuals with CMT2 with a positive family history have a pathogenic variant in MFN2 [Verhoeven et al 2006]. Thus, testing of MFN2 is probably the first genetic test to consider in families with an axonal neuropathy demonstrating male-to-male transmission.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with MFN2 Hereditary Motor and Sensory Neuropathy

System/ConcernEvaluationComment
Peripheral
neuropathy
Neurologic examTo determine extent of weakness & atrophy, pes cavus, gait stability, & sensory loss
EMG w/NCVTo determine axonal form of neuropathy, severity, & involvement of sensory system
MusculoskeletalOrthopedics / physical medicine & rehabilitation / PT/OT evaluationTo incl assessment of:
  • Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
  • Feet for evidence of pes cavus, need for AFOs, specialized shoes
  • Mobility, activities of daily living, & need for adaptive devices
  • Need for handicapped parking
Optic atrophyOphthalmologic exam incl VEPTo incl visual acuity, color vision testing, visual field testing for evidence of central scotomas
Genetic
counseling
By genetics professionals 1To inform affected individuals & their families re nature, MOI, & implications of MFN2-HMSN to facilitate medical & personal decision making
Family support/
Resources
Assess:

AFOs = ankle/foot orthoses; EMG = electromyogram; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; VEP = visual evoked potentials

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Neuropathy is often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [Carter et al 1995]. Treatment is symptomatic and may include the following:

  • Exercise within the individual's capability
  • Daily heel cord stretching exercises to prevent Achilles tendon shortening
  • Special shoes including those with good ankle support
  • Ankle/foot orthoses to correct foot drop and aid walking [Carter et al 1995]
  • Orthopedic surgery to correct severe pes cavus deformity [Holmes & Hansen 1993, Guyton & Mann 2000]
  • Forearm crutches or canes for gait stability
  • Wheelchairs for mobility because of gait instability
  • Exercising and developing coping strategies for fine motor deficits (e.g., buttoning shirts, sliding credit cards)
  • Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents [Carter et al 1998]
  • Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin
  • Career and employment counseling because of persistent weakness of hands and/or feet

Optic atrophy

  • For individuals of all ages. Low vision aids as prescribed by a low vision clinic, and consultation with community vision services
  • For school-age children
    • Individualized education plan (IEP) services that provides specially designed instruction and related services to children who qualify. Vision consultants should be a part of the child's IEP team to support access to academic material.
    • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.

Surveillance

Table 4.

Recommended Surveillance for Individuals with MFN2 Hereditary Motor and Sensory Neuropathy

System/ConcernEvaluationFrequency
Neurologic
  • Neurologic exam
  • Electroneurography of peripheral nerves
  • EMG/ENG
Annually
Musculoskeletal
  • PT assessment (gross motor skills incl gait & strength)
  • OT assessment (fine motor skills)
Annually
ImagingMRI of legs to assess amount & location of fat replacing muscles 1Specialized centers only, every few yrs
Foot examFor pressure sores or poorly fitting footwearAnnually
VisionThose w/o visual manifestationsRoutine ophthalmologic examWhen visual changes occur
Those w/optic
atrophy
Assessment of visual acuity, visual fieldsPer treating ophthalmologist
Assessment of low vision aidsPer treating low vision clinic
For children: assessment of educational needsAnnually
Family support/ResourcesAt each visit

EMG = electromyogram; ENG = electronystagmography; OT = occupational therapy; PT = physical therapy

1.

Agents/Circumstances to Avoid

Obesity, which makes walking more difficult, should be avoided.

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website for an up-to-date list.

Evaluation 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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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

MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is inherited an autosomal dominant manner in about 90% of affected individuals, and in autosomal recessive manner in about 10% of affected individuals.

Semi-dominant inheritance (i.e., a pathogenic variant is associated with mild disease in the heterozygous state and more severe disease in the homozygous or compound heterozygous state) of MFN2-HMSN has been reported in two families [Piscosquito et al 2015, Tomaselli et al 2016].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with autosomal dominant MFN2-HMSN have an affected parent.
  • A proband with MFN2-HMSN may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with MFN2-HMSN caused by a de novo pathogenic variant is unknown.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (somatic and germline mosaicism have been reported [Schon et al 2017]).
  • The family history of some individuals diagnosed with MFN2-HMSN may appear to be negative because of failure to recognize the disorder in family members (a heterozygous family member may be asymptomatic and have only mild findings on examination; see discussion of the CMT neuropathy score in Murphy et al [2011]), early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected [Schon et al 2017].

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 is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial clinical variability has been observed in MFN2-HMSN; a sib who inherits an MFN2 may be more or less severely affected than the proband [Dankwa et al 2019].
  • If the proband has a known MFN2 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Schon et al 2017].
  • When the parents are clinically unaffected, the risk to sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MFN2-HMSN because of the possibility of age-related penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant MFN2-HMSN has a 50% chance of inheriting the MFN2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MFN2 pathogenic variant, his or her family members may be at risk.

Autosomal Recessive Inheritance

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Unless an individual with autosomal recessive MFN2-HMSN has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant MFN2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an MFN2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the MFN2 pathogenic variants in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, at risk of being affected, or at risk of being a carrier of autosomal recessive MFN2-HMSN.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the MFN2 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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
    France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@cmtausa.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.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    Email: info@hnf-cure.org
  • My46 Trait Profile
  • 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 8617
    Fax: 44 (0)191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Netherlands
    Phone: 31 35 5480481
    Fax: 31 35 5480499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.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.

MFN2 Hereditary Motor and Sensory Neuropathy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MFN2 Hereditary Motor and Sensory Neuropathy (View All in OMIM)

601152NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA, WITH OPTIC ATROPHY; HMSN6A
608507MITOFUSIN 2; MFN2
609260CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2A2A; CMT2A2A
617087CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2A2B; CMT2A2B

Molecular Pathogenesis

MFN2 is a key protein in mitochondrial fusion. It has been suggested that pathogenic variants in MFN2 cause mitochondrial stress and a loss of mitochondrial fusion, resulting in axonal damage over time. Other studies have observed axonal transport deficiencies. Additionally, it has been suggested that MFN2 is important for endoplasmic reticulum / mitochondrial tethering and communication. No consistent pathogenic mechanism has yet evolved and thus no common molecular assay for pathogenicity testing exists.

Mechanism of disease causation. The mechanism of disease causation is largely unknown, and may be variant specific. Although, in general, the pathogenic variants associated with autosomal dominant inheritance appear to have a gain of function, loss of function could be the basis of loss of mitochondrial fusion, as suggested in experiments in animal and cell models.

References

Literature Cited

  • Ando M, Hashiguchi A, Okamoto Y, Yoshimura A, Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J, Ishiura H, Umemura A, Maruyama K, Matsushige T, Morishita S, Nakagawa M, Tsuji S, Takashima H. Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. J Peripher Nerv Syst. 2017;22:191–9. [PMC free article: PMC5697682] [PubMed: 28660751]
  • Bissar-Tadmouri N, Nelis E, Züchner S, Parman Y, Deymeer F, Serdaroglu P, De Jonghe P, Van Gerwen V, Timmerman V, Schröder JM, Battaloglu E. Absence of KIF1B mutation in a large Turkish MFN2-HMSN family suggests involvement of a second gene. Neurology. 2004;62:1522–5. [PubMed: 15136675]
  • Capel E, Vatier C, Cervera P, Stojkovic T, Disse E, Cottereau AS, Auclair M, Verpont MC, Mosbah H, Gourdy P, Barraud S, Miquel A, Züchner S, Bonnefond A, Froguel P, Christin-Maitre S, Delemer B, Fève B, Laville M, Robert J, Tenenbaum F, Lascols O, Vigouroux C, Jéru I. MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue. J Clin Lipidol. 2018;12:1420–35. [PubMed: 30158064]
  • Carter GT, Abresch RT, Fowler WM Jr, Johnson ER, Kilmer DD, McDonald CM. Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II. Am J Phys Med Rehabil. 1995;74:S140–9. [PubMed: 7576421]
  • Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998;79:1560–4. [PubMed: 9862301]
  • Chung KW, Cho SY, Hwang SJ, Kim KH, Yoo JH, Kwon O, Kim SM, Sunwoo IN, Züchner S, Choi BO. Early-onset stroke associated with a mutation in mitofusin 2. Neurology. 2008;70:2010–1. [PubMed: 18490623]
  • Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain. 2006;129:2103–18. [PubMed: 16835246]
  • Dankwa L, Richardson J, Motley WW, Scavina M, Courel S, Bardakjian T, Züchner S, Scherer SS. A novel MFN2 mutation causes variable clinical severity in a multi-generational CMT2 family. Neuromuscul Disord. 2019;29:134–7. [PMC free article: PMC6415944] [PubMed: 30642740]
  • Engelfried K, Vorgerd M, Hagedorn M, Haas G, Gilles J, Epplen JT, Meins M. Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med Genet. 2006;7:53. [PMC free article: PMC1524942] [PubMed: 16762064]
  • Feely SM, Laura M, Siskind CE, Sottile S, Davis M, Gibbons VS, Reilly MM, Shy ME. MFN2 mutations cause severe phenotypes in most patients with MFN2-HMSN. Neurology. 2011;76:1690–6. [PMC free article: PMC3100135] [PubMed: 21508331]
  • Gentile L, Russo M, Fabrizi GM, Taioli F, Ferrarini M, Testi S, Alfonzo A, Aguennouz M, Toscano A, Vita G, Mazzeo A. Charcot-Marie-Tooth disease: experience from a large Italian tertiary neuromuscular center. Neurol Sci. 2020;41:1239–43. [PubMed: 31902012]
  • 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]
  • Hikiami R, Yamashita H, Koita N, Jingami N, Sawamoto N, Furukawa K, Kawai H, Terashima T, Oka N, Hashiguchi A, Takashima H, Urushitani M, Takahashi R. Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease. J Hum Genet. 2018;63:89–92. [PubMed: 29215088]
  • Holmes JR, Hansen ST Jr. Foot and ankle manifestations of Charcot-Marie-Tooth disease. Foot Ankle. 1993;14:476–86. [PubMed: 8253442]
  • Hsu YH, Lin KP, Guo YC, Tsai YS, Liao YC, Lee YC. Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan. Ann Clin Transl Neurol. 2019;6:1090–101. [PMC free article: PMC6562034] [PubMed: 31211173]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Klein CJ, Kimmel GW, Pittock SJ, Engelstad JE, Cunningham JM, Wu Y, Dyck PJ. Large kindred evaluation of mitofusin 2 novel mutation, extremes of neurologic presentations, and preserved nerve mitochondria. Arch Neurol. 2011;68:1295–302. [PMC free article: PMC3543870] [PubMed: 21987543]
  • Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of MFN2-HMSN with mutations in the mitofusin 2 gene. Neurology. 2005;65:197–204. [PubMed: 16043786]
  • Lin HP, Ho KWD, Jerath NU. Late onset CMT2A in a family with an MFN2 variant: c.2222T>G (p.Leu741Trp). J Neuromuscul Dis. 2019;6:259–61. [PubMed: 31127728]
  • Milley GM, Varga ET, Grosz Z, Nemes C, Arányi Z, Boczán J, Diószeghy P, Molnár MJ, Gál A. Genotypic and phenotypic spectrum of the most common causative genes of Charcot-Marie-Tooth disease in Hungarian patients. Neuromuscul Disord. 2018;28:38–43. [PubMed: 29174527]
  • Morrow JM, Evans MRB, Grider T, Sinclair CDJ, Thedens D, Shah S, Yousry TA, Hanna MG, Nopoulos P, Thornton JS, Shy ME, Reilly MM. Validation of MRC Centre MRI calf muscle fat fraction protocol as an outcome measure in CMT1A. Neurology. 2018;91:e1125–e29. [PMC free article: PMC6161551] [PubMed: 30120135]
  • Muglia M, Zappia M, Timmerman V, Valentino P, Gabriele AL, Conforti FL, De Jonghe P, Ragno M, Mazzei R, Sabatelli M, Nicoletti G, Patitucci AM, Oliveri RL, Bono F, Gambardella A, Quattrone A. Clinical and genetic study of a large Charcot-Marie-Tooth type 2A family from southern Italy. Neurology. 2001;56:100–3. [PubMed: 11148244]
  • Murphy SM, Herrmann DN, McDermott MP, Scherer SS, Shy ME, Reilly MM, Pareyson D. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011;16:191–8. [PMC free article: PMC3754828] [PubMed: 22003934]
  • Oh JH, Lee HS, Cha DM, Kang SY. Hereditary Motor and Sensory Neuropathy Type VI with Bilateral Middle Cerebellar Peduncle Involvement. Exp Neurobiol. 2014;23:266–9. [PMC free article: PMC4174619] [PubMed: 25258575]
  • Piscosquito G, Saveri P, Magri S, Ciano C, Di Bella D, Milani M, Taroni F, Pareyson D. Mutational mechanisms in MFN2-related neuropathy: compound heterozygosity for recessive and semidominant mutations. J Peripher Nerv Syst. 2015;20:380–6. [PubMed: 26306937]
  • Polke JM, Laurá M, Pareyson D, Taroni F, Milani M, Bergamin G, Gibbons VS, Houlden H, Chamley SC, Blake J, Devile C, Sandford R, Sweeney MG, Davis MB, Reilly MM. Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology. 2011;77:168–73. [PMC free article: PMC3140074] [PubMed: 21715711]
  • Saito M, Hayashi Y, Suzuki T, Tanaka H, Hozumi I, Tsuji S. Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (MFN2-HMSN) and the clinical features of MFN2-HMSN. Neurology. 1997;49:1630–5. [PubMed: 9409358]
  • Sawyer SL, Cheuk-Him Ng A, Innes AM, Wagner JD, Dyment DA, Tetreault M, Majewski J, Boycott KM, Screaton RA, Nicholson G, et al. Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy. Hum Mol Genet. 2015;24:5109–14. [PubMed: 26085578]
  • Schon K, Spasic-Boskovic O, Brugger K, Graves TD, Abbs S, Park SM, Ambegaonkar G, Armstrong R. Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child. Neurogenetics. 2017;18:49–55. [PMC free article: PMC5243894] [PubMed: 28063088]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • Sun B, Chen Z, Ling L, Yang F, Huang X. Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients. J Peripher Nerv Syst. 2017;22:13–18. [PubMed: 27862672]
  • Tomaselli PJ, Rossor AM, Polke JM, Poh R, Blake J, Reilly MM. Semi-dominant mutations in MFN2-related neuropathy and implications for genetic counselling. J Peripher Nerv Syst. 2016;21:52–4. [PubMed: 26930221]
  • Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, Goemans N, Auer-Grumbach M, Robberecht W, Milic Rasic V, Nevo Y, Tournev I, Guergueltcheva V, Roelens F, Vieregge P, Vinci P, Moreno MT, Christen HJ, Shy ME, Lupski JR, Vance JM, De Jonghe P, Timmerman V. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129:2093–102. [PubMed: 16714318]
  • Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA. CMT with pyramidal features. Charcot-Marie-Tooth. Neurology. 2003;60:696–9. [PubMed: 12601114]
  • Zhu D, Kennerson ML, Walizada G, Züchner S, Vance JM, Nicholson GA. Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology. 2005;65:496–7. [PubMed: 16087932]
  • Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006;59:276–81. [PubMed: 16437557]
  • Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004;36:449–51. [PubMed: 15064763]

Chapter Notes

Revision History

  • 14 May 2020 (bp) Comprehensive update posted live
  • 1 August 2013 (me) Comprehensive update posted live
  • 10 June 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
  • 12 September 2007 (me) Comprehensive update posted live
  • 23 January 2006 (cd) Revision: prenatal diagnosis for MFN2 mutations clinically available
  • 18 February 2005 (me) Review posted live
  • 13 September 2004 (sz) Original submission
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