Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median ...Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (118200) and CMT1A (118220) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (214400) and CMTX1 (302800) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively. Several forms of axonal CMT neuropathies caused by mutations in different genes or at different loci have been described, including CMT2B (600882), CMT2B1 (605588), CMT2B2 (605589), CMT2C (606071), CMT2D (601472), CMT2E (607684), CMT2F (606595), CMT2G (608591), CMT2H (607731), CMT2I (607677), CMT2J (607736), and CMT2K (607831)
Saito et al. (1997) reported a Japanese family (family 693) in which 11 members spanning 4 generations had CMT2A2 inherited in an autosomal dominant pattern. The proband was a 45-year-old woman who developed a foot deformity, limping gait, and ...Saito et al. (1997) reported a Japanese family (family 693) in which 11 members spanning 4 generations had CMT2A2 inherited in an autosomal dominant pattern. The proband was a 45-year-old woman who developed a foot deformity, limping gait, and difficulty running at age 8 years. At age 20, she had difficulty climbing stairs. On examination at age 45, she had bilateral pes cavus, hammertoes, and mild muscle weakness of the anterior tibial, peroneal, and posterior tibial muscles without atrophy. She had lower limb hyporeflexia and ankle areflexia, as well as mildly decreased sensation of pain and vibration in her feet. Median nerve motor conduction velocity was normal, but sural nerve sensory action potentials could not be evoked. Nerve biopsy was not performed. Zuchner et al. (2004) identified a heterozygous mutation in the MFN2 gene (608507.0001) in affected members of this family. Muglia et al. (2001) reported a large pedigree from southern Italy with CMT2A2. Affected family members had distal muscle weakness and wasting with reduced or absent reflexes and mild distal sensory loss. Nerve biopsies in 2 members confirmed a loss of large myelinated fibers but no myelin abnormalities. Vucic et al. (2003) and Zhu et al. (2005) reported a family in which 11 members had CMT2A2. Age at onset ranged from 4 to 20 years. In addition to typical signs and symptoms of CMT, most patients also had pyramidal signs, including extensor plantar responses, mild increases in muscle tone, and preserved or increased reflexes. However, there was no spasticity. The phenotype in this family indicated that CMT2A can be associated with pyramidal signs. Lawson et al. (2005) reported 3 unrelated Utah families with CMT2A2 caused by 3 different mutations, respectively, in the MFN2 gene. The phenotypes were consistent with typical axonal CMT, with distal predominant lower extremity weakness and wasting, sensory loss, and areflexia. In the largest family, 6 mutation carriers had signs and symptoms mild enough that they had not sought medical attention. The findings indicated that in some families with CMT2A2 as many as 25% of individuals with mutations may be asymptomatic and have a normal electrophysiologic examination, although a detailed neuromuscular examination may suggest the trait. Nicholson et al. (2008) reported 3 unrelated adult patients with severe early-onset axonal neuropathy associated with compound heterozygous or homozygous (see, e.g., 608507.0013) mutations in the MFN2 gene. The patients presented at age 2 to 3 years with clubfoot, talipes, or increased falls. All had muscle weakness and wasting of the upper and lower limbs, distal sensory loss, and normal or mildly decreased nerve conduction velocity. Two patients were slightly deaf, and 2 had spinal deformities. All parents were heterozygous for the mutations and were either asymptomatic or mildly symptomatic with some signs of peripheral neuropathy. Nicholson et al. (2008) concluded that inheritance in these families was semidominant and that the parents showed reduced penetrance, although the disorder in the offspring presented as apparently autosomal recessive. The findings indicated that biallelic MFN2 mutations can result in a more severe phenotype and that heterozygous MFN2 mutations may show incomplete penetrance. - Clinical Variability Del Bo et al. (2008) reported an Italian father and 2 sons with peripheral neuropathy and a highly variable phenotype. The father had a symmetric axonal predominantly motor polyneuropathy, spastic gait, and pes cavus, consistent with CMT2A2, as well as impaired nocturnal vision and sensorineural hearing loss, consistent with HMSN6. He also showed cognitive decline first noted in his forties. Both sons had delayed motor and language development, decreased IQ, steppage gait, distal muscle weakness and atrophy, and axonal sensorimotor neuropathy at ages 10 and 7 years, respectively. One son also had optic nerve dysfunction. MR spectroscopy (MRS) in the father suggested a defect in mitochondrial energy metabolism in the occipital cortex. Molecular analysis identified a heterozygous mutation in the MFN2 gene (608507.0014) in all 3 individuals. Del Bo et al. (2008) suggested that central nervous system involvement and cognitive impairment may be other phenotypic features of MFN2 mutations. Boaretto et al. (2010) reported 2 sisters and a brother with a severe form of adult-onset axonal CMT associated with a fatal subacute encephalopathy characterized by vomiting, nystagmus, chorea, clouded consciousness, and dysautonomia. At age 50, after colectomy, 1 sister developed encephalopathy. Postmortem examination of this patient showed vasculonecrotic lesions in the upper brainstem and periaqueductal gray matter. Their father had a similar course and died at age 61. Genetic analysis identified a heterozygous splice site mutation in the MFN2 gene (608507.0016), which was not found in 200 control chromosomes. An unaffected 64-year-old sister also carried the mutation, indicating incomplete penetrance. Boaretto et al. (2010) noted the unusual encephalopathy present in this family, and suggested that the nature of the mutation may have put sensitive areas of the brain in a precarious energetic equilibrium. However, unknown genetic, epigenetic factors, or environmental factors likely played a role in the phenotype
Zuchner et al. (2004) identified mutations in the MFN2 gene (608507.0001-608507.0006) in affected members of several families with CMT2A2, including 1 family reported by Bissar-Tadmouri et al. (2004), 1 reported by Muglia et al. (2001), and 1 (family 693) ...Zuchner et al. (2004) identified mutations in the MFN2 gene (608507.0001-608507.0006) in affected members of several families with CMT2A2, including 1 family reported by Bissar-Tadmouri et al. (2004), 1 reported by Muglia et al. (2001), and 1 (family 693) reported by Saito et al. (1997). In 11 affected members of the family reported by Vucic et al. (2003), Zhu et al. (2005) identified a heterozygous mutation in the MFN2 gene (608507.0008). Chung et al. (2006) identified 10 pathogenic MFN2 mutations (see, e.g., 608507.0004; 608507.0009; 608507.0011) in 26 patients from 15 (24.2%) of 62 Korean families with CMT2A2 or HMSN VI. There were 2 main groups of patients, including those with early onset before 10 years and those with late onset after age 10 years. Those with early onset had a severe disorder, often with scoliosis and contractures, whereas those with later onset had a milder disorder and a higher frequency of unusual findings such as tremor, pain, and hearing loss. The severity of the disorder tended to be the same within families, suggesting a genotype/phenotype correlation. Cho et al. (2007) identified mutations in the MFN2 gene in 4 (33%) of 12 unrelated Korean patients with CMT type 2. Two of the 4 patients had a family history of the disorder. Calvo et al. (2009) identified 20 different missense mutations, including 10 novel mutations, in the MFN2 gene in 20 of 150 probands with CMT and a nerve conduction velocity (NCV) of 25 m/s or greater. Eighteen of the patients had been previously reported. The mutation frequency was 17.8% (19 of 107 patients) in CMT2 and 2.3% (1 of 43) with CMT1 (NCV less than 38 m/s). Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance; the remaining 5 patients were sporadic cases with heterozygous mutations. The phenotypes varied from mild forms to early-onset severe forms, and additional features, such as pyramidal signs or vasomotor dysfunction, were encountered in 8 patients (32%). The study indicated that MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. Calvo et al. (2009) suggested that testing for mutations in MFN2 showed be a first-line analysis in axonal CMT regardless of the mode of inheritance or the severity of the peripheral neuropathy. Casasnovas et al. (2010) identified 9 different heterozygous MFN2 mutations, including 4 novel mutations, in 24 patients from 14 different Spanish families with CMT2A2. Six (42.8%) of 14 families carried the same mutation (R468H; 608507.0015). Overall, MFN2 mutations were identified in 16% of the total cohort of 85 Spanish families with axonal CMT, and Casasnovas et al. (2010) concluded that MFN2 is the most frequent cause of axonal CMT in this population
In 14 (11%) of 127 Japanese patients with axonal CMT, Abe et al. (2011) found mutations in the MFN2 gene, which represented the most common molecular cause. A molecular basis for the disease could not be found in 100 ...In 14 (11%) of 127 Japanese patients with axonal CMT, Abe et al. (2011) found mutations in the MFN2 gene, which represented the most common molecular cause. A molecular basis for the disease could not be found in 100 Japanese patients with axonal CMT. Lin et al. (2011) identified MFN2 mutations in 5 (13.9%) of 36 Taiwanese families of Han Chinese descent with CMT2
Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) is a classic axonal peripheral sensorimotor neuropathy diagnosed by molecular genetic testing of MFN2....
DiagnosisClinical DiagnosisCharcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) is a classic axonal peripheral sensorimotor neuropathy diagnosed by molecular genetic testing of MFN2.No specific findings distinguish CMT2A from other types of CMT2. Typical findings include the following:Involvement of the lower extremities earlier and more severely than the upper extremitiesInvolvement of the distal upper extremities as the neuropathy progressesMore prominent motor deficits than sensory deficitsNormal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs) [Saito et al 1997, Züchner et al 2004]Molecular Genetic TestingGene. MFN2 is the primary gene known to be associated with CMT2A.Other genes. It is possible (though at present highly unlikely) that KIF1B is involved in rare families with CMT2A1. KIF1B is in the same chromosomal locus as MFN2. In a single family from Japan, a functionally significant mutation in KIF1B segregates with the clinical phenotype; of note, studies of MFN2 in this family were inconclusive [Zhao et al 2001]. However, a mutation in KIF1B was not confirmed in a second family [Bissar-Tadmouri et al 2004, Züchner et al 2004].Clinical testingSequence analysisMFN2. Sequence analysis detects a mutation in nearly 100% of individuals with CMT2A2. KIF1B. Except for the original single family reported, no family or individual has been reported with a KIF1B mutation [Zhao et al 2001].Table 1. Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 2AView in own windowGeneTest MethodMutations DetectedProportion of CMT2A Attributed to Mutations in This GeneMutation Detection Frequency by Gene and Test Method 1 Test AvailabilityMFN2Sequence analysisMFN2 sequence variantsNearly 100%Nearly 100%Clinical KIF1BKIF1B sequence variantsRareUnknownClinical 1. The ability of the test method used to detect a mutation that is present in the indicated geneInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish the diagnosis in a proband, identification of a disease-causing mutation in MFN2 or KIF1B is necessary.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMFN2. No phenotypes other than the CMT2A2 phenotype discussed in Clinical Description have been associated with mutations in MFN2.KIF1B. No phenotypes associated with mutation in KIF1B have been reported other than that described in the one family found to have this mutation [Zhao et al 2001].
The age at onset and disease progression of Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) vary within and among families; onset ranges from age one year to the sixth decade. Most individuals develop symptoms in the first or second decade. The initial finding is often foot drop or foot weakness. Pes cavus foot deformity may occur....
Natural HistoryThe age at onset and disease progression of Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) vary within and among families; onset ranges from age one year to the sixth decade. Most individuals develop symptoms in the first or 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.Some individuals with MFN2 mutations are asymptomatic and have only mild findings on examination; however, those might eventually convert to late-onset cases [Lawson et al 2005].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]. 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 was reported by Züchner et al [2006] and confirmed by Chung et al [2006] and Verhoeven et al [2006].Note: The association of CMT2A and optic atrophy is also known as hereditary motor and sensory neuropathy VI (HMSN VI) (see Nomenclature).CMT2 with pyramidal signs, also known as HMSN VII, has been associated with MFN2 mutations [Zhu et al 2005]. HMSN VII is characterized by an axonal CMT phenotype with mild pyramidal signs, including extensor plantar responses, mild increase in tone, and preserved or increased reflexes, but no spastic gait [Vucic et al 2003].The disease course is progressive. Although some individuals become dependent on crutches or a wheelchair, most do not [Muglia et al 2001]. Life span is usually not reduced.Neuroimaging. Periventricular and subcortical white matter lesions on brain MRI have been reported in a few individuals [Chung et al 2006, Züchner et al 2006].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].
No apparent genotype-phenotype correlation has been reported except in one family in which truncation of the protein led to a more severe phenotype with visual impairment [Züchner et al 2006]....
Genotype-Phenotype CorrelationsNo apparent genotype-phenotype correlation has been reported except in one family in which truncation of the protein led to a more severe phenotype with visual impairment [Züchner et al 2006].
See Charcot-Marie-Tooth Hereditary Neuropathy Overview and Charcot-Marie-Tooth Hereditary Neuropathy Type 2....
Differential DiagnosisSee Charcot-Marie-Tooth Hereditary Neuropathy Overview and Charcot-Marie-Tooth Hereditary Neuropathy Type 2.All CMT forms in which axonal phenotypes have been reported, including CMT1A (caused by mutations in PMP22), CMT1B (caused by mutations in MPZ), and CMTX (caused by mutations in GJB1, the gene encoding the protein connexin 32), need to be considered in the differential diagnosis of CMT2A.MFN2 mutations may prove to be the most common cause of autosomal dominant CMT2. As many as one third of all individuals with CMT2 with a positive family history have a mutation 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.
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A), the following evaluations are recommended:Neurologic examinationEMG with NCVVisual evoked potentialsTreatment of ManifestationsThe affected individual 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:Daily heel cord stretching exercises to prevent Achilles tendon shorteningSpecial shoes, including those with good ankle supportAnkle/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 stabilityWheelchairs for mobility because of gait instabilityExercise within the individual's capabilityTreatment 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 gabapentinCareer and employment counseling because of persistent weakness of hands and/or feetSurveillanceAnnual neurologic evaluation of gait, strength, and visual acuity is appropriate.Agents/Circumstances to AvoidObesity is to be avoided because it makes walking more difficult.Medications that 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 asymptomaticOther 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 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationDyck et al [1982], Donaghy et al [2000], and Ginsberg et al [2004] have described a few individuals with CMT1 and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin has produced variable levels of improvement. No similar report on CMT2A exists.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 2A: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCMT2A2MFN21p36.22Mitofusin-2IPN Mutations, MFN2 MFN2 homepage - Leiden Muscular Dystrophy pagesMFN2CMT2A1KIF1B1p36.22Kinesin-like protein KIF1BIPN Mutations, KIF1B KIF1B homepage - Leiden Muscular Dystrophy pagesKIF1BData 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 2A (View All in OMIM) View in own window 118210CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A1; CMT2A1 605995KINESIN FAMILY MEMBER 1B; KIF1B 608507MITOFUSIN 2; MFN2 609260CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2Molecular Genetic PathogenesisThe disease mechanism leading to CMT is unknown.MFN2Normal allelic variants. MFN2 has 17 exons and 4,546 necleotides in the open reading frame.Pathologic allelic variants. To date, more than 50 mutations have been reported. The majority were missense muations; frameshift and nonsense mutations have also been reported [Züchner et al 2004, Verhoeven et al 2006].Normal gene product. MFN2 encodes a large GTPase of 757 amino acids that is situated at the outer mitochondrial membrane [Rojo et al 2002]. It has been shown that MFN2 accounts for the fusion/fission balance of mitochondria [Santel & Fuller 2001]. Recently, evidence for direct involvement of MFN2 in fusion of mitochondria has been reported [Koshiba et al 2004]. The gene is ubiquitously expressed [Santel & Fuller 2001].Abnormal gene product. Most mutations are in the GTPase domain, but other parts of the protein are also affected. The GTPase domain may be crucial for the development of peripheral neuropathy. Mutations may affect both mitochondrial fusion and energy metabolism [Pich et al 2005]. Baloh et al [2007] reported altered axonal mitochondrial transport resulting from CMT2A-related MFN2 mutations.KIF1BNormal allelic variants. KIF1B has 41 exons. It encodes at least two major splice variants, KIF1Bα and KIF1Bβ. The gene consists of 10,551 nucleotides in an open reading frame.Pathologic allelic variants. One pathogenic mutation, p.Gln98Leu, segregating in a small pedigree, has been reported [Zhao et al 2001].Normal gene product. The protein has 1,770 amino acids and belongs to the kinesin super-family of large motor proteins. These proteins carry organelles (e.g., vesicles, mitochondria) along microtubules within axons of nerves. Knockout mice develop symptoms comparable to a peripheral neuropathy [Zhao et al 2001].Abnormal gene product. Vero cells transfected with the p.Gln98Leu mutant showed reduced transport of KIF1B to the periphery of the cells. Knockout mice developed a phenotype consistent with peripheral neuropathy.