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.

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):

• A heterozygous pathogenic variant involving MFN2 (~90% of affected individuals) [Pipis et al 2020]
• Biallelic MFN2 pathogenic variants (~10% of affected individuals) [Pipis et al 2020]

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.

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 2020].

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 2020].

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).

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]).

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.

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

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.

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, the parent 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, the parent's family members may be at risk.

Autosomal Recessive Inheritance

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/preimplantation genetic 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.

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.

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.

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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