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Charcot-Marie-Tooth Neuropathy Type 2

Synonyms: CMT2; Charcot-Marie-Tooth Disease, Axonal Type; HMSN2; Hereditary Motor and Sensory Neuropathy 2. Includes: CMT2A1, CM2A2, CMT2B, CMT2B1, CMT2B2, CMT2C, CMT2D, CMT2E/1F, CMT2F, CMT2G, CMT2I/J, CMT2H/K, CMT2L, CMT2N, CMT2O, CMT2P
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: April 3, 2014.

Summary

Disease characteristics. Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. CMT2 is clinically similar to CMT1, although typically less severe. Peripheral nerves are not enlarged or hypertrophic. The subtypes of CMT2 are similar clinically and distinguished only by molecular genetic findings.

Diagnosis/testing. The diagnosis is based on clinical findings and EMG/NCV characteristics. The 15 genes in which mutations are known to cause CMT2 subtypes are KIF1B (CMT2A1), MFN2 (CMT2A2), RAB7A (formerly RAB7) (CMT2B), LMNA (CMT2B1), MED25 (CMT2B2), TRPV4 (CMT2C), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/J), GDAP1 (CMT2H/K), HSPB8 (CMT2L), AARS (CMT2N), DYNC1H1 (CMT2O), and LRSAM1 (CMT2P).

Management. Treatment of manifestations: Treatment by a team including a neurologist, physiatrists, orthopedic surgeons, physical, and occupational therapist; special shoes and/or ankle/foot orthoses (AFO) 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; symptomatic treatment of pain, depression, sleep apnea, restless legs syndrome.

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

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

Agents/circumstances to avoid: Obesity, which makes ambulation more difficult; medications known to cause nerve damage (e.g., vincristine, isoniazid, nitrofurantoin).

Other: Career and employment counseling.

Genetic counseling. CMT2B1, CMT2B2, and CMT2H/K are inherited in an autosomal recessive manner; all other subtypes of CMT2 are inherited in an autosomal dominant manner. Most probands with autosomal dominant subtypes of CMT2 have inherited the disease-causing mutation from an affected parent. The offspring of an affected individual with autosomal dominant CMT2 are at a 50% risk of inheriting the altered gene.

Diagnosis

Clinical Diagnosis

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is diagnosed clinically in individuals with the following:

  • A progressive peripheral motor and sensory neuropathy
  • Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
  • EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
  • Greatly reduced compound motor action potentials (CMAP)
  • A family history consistent with autosomal dominant inheritance

Testing

Nerve biopsy does not show the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 (CMT1) but instead shows loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments.

Molecular Genetic Testing

Genes. Fifteen genes in which mutations are known to cause subtypes of CMT2 have been identified [Züchner & Vance 2006b] (Table 1).

Table 1. Genes Associated with CMT2 Subtypes

1. Found in one family

2. Represents approximately 20%-30% of CMT2

Evidence for locus heterogeneity. Another locus for CMT2 has been mapped; no gene has yet been identified (see Table 2).

Table 2. CMT2: Other Locus

CMT2 SubtypeChromosomal LocusReference
CMT2G12q12-q13.3Nelis et al [2004]

Clinical testing (CMT2A1, CMT2A2, CMT2B, CMT2B1, CMT2B2, CMT2C, CMT2D, CMT2E/1F, CMT2F, CMT2I/J, CMT2H/K, CMT2L, CMT2N)

Table 3. Summary of Molecular Genetic Testing Used in CMT2

Gene 1 / Locus NameTest MethodMutations Detected 2Proportion of CMT2 Attributed to Mutations in This GeneMutation Detection Frequency 3
KIF1B / CMT2A1Sequence analysisSequence variants 4 RareUnknown
MFN2 / CMT2A2Sequence analysis and mutation scanning 5,6Sequence variants 4 20%Unknown
Deletion/duplication analysis 6Exonic or whole-gene deletions
RAB7A / CMT2BSequence analysisSequence variants 4 RareUnknown
LMNA / CMT2B1Sequence analysisSequence variants 4 RareUnknown
Deletion/duplication analysis 7Exonic or whole-gene deletionsUnknown, none reported
MED25 / CMT2B2Sequence analysis Sequence variants 4RareUnknown
Mutation scanning of select exons 5Sequence variants in exon4,5
Targeted mutation analysisp.Ala335Val
TRPV4 / CMT2CSequence analysisSequence variants 4RareUnknown
Sequence analysis of select exons Sequence variants in exons 5,6 4,5RareUnknown
GARS / CMT2DSequence analysisSequence variants 4 RareUnknown, none reported
Deletion/duplication analysis 7Exonic or whole-gene deletions
NEFL / CMT2E/1FSequence analysisSequence variants 4 RareUnknown
HSPB1 / CMT2FSequence analysisSequence variants 4 RareUnknown, none reported
Deletion/duplication analysis 7Exonic or whole-gene deletions
Unknown / CMT2GLinkage analysisNot applicableRareNot applicable
MPZ / CMT2I/JSequence analysis, mutation scanning 6Sequence variants 4RareUnknown
Deletion/duplication analysis 7Deletions or duplications Unknown, none reported
GDAP1 / CMT2H/KSequence analysisSequence variants 4 RareUnknown
HSPB8 / CMT2LSequence analysisSequence variants 4 RareUnknown
Deletion/duplication analysis 7Exonic or whole-gene deletions Unknown, none reported
AARS / CMT2NSequence analysisSequence variants 4RareUnknown
DYNC1H1 / CMT2OSequence analysisSequence variants 4RareUnknown
LRSAM1 / CMT2PSequence analysis of select exonsSequence variants in exon 25 4RareUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Selected exons for testing may vary among laboratories.

6. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies, although mutation scanning detection rates may vary considerably among laboratories as that method is highly dependent on details of the methodology employed.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

One genetic testing strategy is serial single gene molecular genetic testing based on the individual’s family history and neurophysiologic data [England et al 2009, Saporta et al 2011]. The relative frequencies of various CMT2 subtypes are shown in Figure 1.

Figure 1

Figure

Figure 1. Genetic diagnoses in CMT and related disorders

From Rossor et al [2013]; reprinted with permission

Specifically, to establish the diagnosis of a CMT2 subtype the proband should first be tested for mutations in MFN2, MPZ, and GJB1 (encoding connexin 32), as mutations in these genes are most commonly responsible for this syndrome, probably accounting for 20%-25% of cases [Züchner & Vance 2006b, Bienfait et al 2007, Saporta et al 2011].

Note: If there is male-to-male transmission in the family it is not necessary to test for mutations in GJB1, an X-linked gene.

If no mutation is identified in these three genes, many neurologists do no further genetic testing because the other known genes are quite rare and many genetic causes remain to be discovered. Affected individuals who wish to exhaust all possibilities may want to proceed with the other tests relevant to CMT2 (e.g., NEFL, GDAP1, RAB7A, MED25, TRPV4, AARS). If the phenotype includes vocal cord paresis, molecular genetic testing of GDAP1 and TRPV4 is appropriate.

An alternative genetic testing strategy is use of a multi-gene panel that includes genes associated with CMT2 and other genes of interest (see Differential Diagnosis) [Rossor et al 2013]. Panels exist for dominantly and recessively inherited CMTs as well as demyelination and axonal forms. Larger (all-inclusive) panels may also be available. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

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

Clinical Description

Natural History

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is a disorder of peripheral nerves in which the motor system is more prominently involved than the sensory system, although both are involved [Pareyson & Marchesi 2009]. The affected individual typically has slowly progressive weakness and atrophy of distal muscles in the feet and/or hands usually associated with depressed tendon reflexes and mild or no sensory loss. The clinical syndrome overlaps extensively with CMT1. With the exception of CMT2B, CMT2 tends to be less disabling and to cause less sensory loss than CMT1 [Bienfait et al 2006, Pareyson et al 2006].

Affected individuals usually become symptomatic between ages five and 25 years [Bienfait et al 2006], though onset ranges from infancy with delayed walking to after the third decade. The typical presenting symptom is weakness of the feet and ankles. The initial physical findings are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle. Baets et al [2011] review the clinical presentations in the first year of life.

The adult with CMT2 typically has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance) and absent tendon reflexes in the lower extremities. However, brisk tendon reflexes and extensor plantar responses have been reported as well as asymmetric muscle atrophy in up to 15% of affected individuals [Bienfait et al 2007].

Atrophy of intrinsic hand muscles is less frequently present and tendon reflexes may be intact in the upper limbs.

Proximal muscles usually remain strong. Brisk tendon reflexes and extensor plantar responses have been reported [Bienfait et al 2007].

Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact. Pain, especially in the feet, is reported by about 20%-40% of affected individuals [Gemignani et al 2004]. Hearing impairment has been reported [Bienfait et al 2006].

Optic atrophy may occur in CMT2A [Züchner et al 2006].

A few individuals have vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing [Dematteis et al 2001, Sulica et al 2001].

Restless legs and sleep apnea have been associated with CMT2 [Aboussouan et al 2007].

CMT2 is progressive over many years, but affected individuals experience long plateau periods without obvious deterioration. In some, the disease can be so mild as to go unrecognized by the affected individual and physician. The disease does not decrease life span.

CMT2 subtypes

Neuropathology. The disease process is presumed to occur in the axon or cytoplasm of the anterior horn cell neuron. Anterior horn cell loss has been found in two autopsies [Schroder 2006].

In CMT2E, electron microscopy has shown giant axons with accumulation of disorganized neurofilaments [Fabrizi et al 2004].

Genotype-Phenotype Correlations

Few specific genotype-phenotype correlations are known. Considerable variability of phenotype has been observed within families with CMT2A [Züchner et al 2004a, Klein et al 2011b].

Optic atrophy is associated with mutations in MFN2 [Verhoeven et al 2006, Züchner et al 2006].

Some mutations in TRPV4 are associated with diseases of bone [Verma et al 2010].

Penetrance

Penetrance is usually nearly complete. However, because some subtypes of CMT2 are associated with adult onset of symptoms, penetrance is age dependent.

Nomenclature

CMT2A. This disorder is also known as hereditary motor and sensory neuropathy VI (HMSN VI).

CMT2 with pyramidal signs, also known as hereditary motor and sensory neuropathy V (HMSN V), has been associated with MFN2 mutations [Zhu et al 2005] and with mutations in BSCL2 [Bienfait et al 2007] (see BSCL2-Related Neurologic Disorders).

CMT2C. Previously this has sometimes been called scapuloperoneal spinal muscular atrophy.

CMT2E/1F. Some individuals with mutations in NEFL, which typically cause CMT2E, may have slow NCVs, resulting in a diagnosis of CMT1F. To accommodate these two phenotypes associated with mutations in NEFL, the designation CMT2E/1F has been used.

Prevalence

The overall prevalence of hereditary neuropathies is estimated at approximately 3:10,000 population. About 30% of these individuals (1:10,000) may have CMT2. The prevalence of the various subtypes of CMT2 is unknown. CMT2A represented 3.4%-16% of all CMT families in Norway and Spain respectively [Braathen et al 2010, Casasnovas et al 2010].

In a large study of German individuals with a CMT2 phenotype (776), Gess et al [2013] found the following percentages: 11% had CMTX1, 8% had CMT2Aand 6% had the rare giant axonal neuropathy. Among those with CMT2, 35% had a genetic diagnosis.

Rossor et al [2013] show the prevalence of various subtypes of CMT2 and note that 75% of cases have no known associated gene. See Figure 1.

Differential Diagnosis

See CMT Overview, particularly to exclude potentially treatable causes of acquired neuropathy.

Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) can sometimes be difficult to distinguish from chronic idiopathic axonal neuropathy.

Bienfait et al [2006] found extensive clinical overlap between individuals with CMT1A and CMT2, while noting that people with CMT1A are more likely to have earlier-onset disease, foot deformity, and total areflexia.

A median motor NCV of 38 m/s is often used as a threshold for differentiating CMT1 from CMT2; however, the CMT2 phenotype can result from mutations in genes primarily associated with CMT1 and CMTX1 [Gutierrez et al 2000, Young et al 2001, Shy et al 2004].

CMT2C resembles two other disorders:

Several different types of autosomal dominant hereditary axonal neuropathy may cause predominantly sensory symptoms, including the "burning feet syndrome" [Stogbauer et al 1999, Auer-Grumbach et al 2003]. Families with hereditary sensory neuropathy (including hereditary sensory neuropathy type 1 caused by mutations in SPTLC1 [Bejaoui et al 2001]) usually do not have motor symptoms such as muscle weakness, but findings can sometimes overlap with CMT2B.

Bellone et al [2002] reported a family with autosomal dominant mutilating neuropathy that was not linked to the CMT2B locus or the HSN1 locus.

The CMT2 phenotype may sometimes be associated with signs of spasticity (e.g., hyperactive tendon reflexes and/or Babinski signs). This phenotype has sometimes been referred to as HMSN V. Two affected families have been reported by Vucic et al [2003]. One gene associated with this phenotype has been identified (see BSCL2-Related Neurologic Disorders).

Another form of autosomal dominant motor and sensory neuropathy from Okinawa has been mapped to 3q13 [Takashima et al 1999]. The relationship of this entity to CMT2B, which is linked to a similar region, is undetermined. Ishiura et al [2012] have found mutations in TFG causing hereditary motor and sensory neuropathy with proximal dominant involvement. Lee et al [2013a] have found the same mutation in TFG in a Korean family with proximal dominant HMSN.

Females with CMTX1 (GJB1, encoding connexin 32) may have a CMT2 phenotype.

Boyer et al [2011] have reported heterozygous mutation of INF2 associated with childhood-onset CMT syndrome later complicated by renal glomerulosclerosis. Nerve conductions have varied from moderately slow to normal. Intellectual disability and hearing loss are also reported [Mademan et al 2013].

  • Lopez-Bigas et al [2001] have described an autosomal dominant neuropathy associated with hearing impairment caused by a mutation in GJB3, encoding the protein connexin 31. Although the sural nerve pathology showed demyelination compatible with CMT1, the nerve condition velocities were not markedly slow and may suggest a clinical diagnosis of CMT2.
  • Weedon et al [2011] have described a large four-generation family with childhood-onset axonal CMT and a missense mutation (p.His306Arg) in DYNC1H1, the gene encoding cytoplasmic dynein 1 heavy chain 1.
  • Mutations in DNM2 (dynamin 2) usually cause centronuclear myopathy, but there may be an overlap with a predominantly CMT2 presentation [Bohm et al 2012].
  • Klein et al [2011a] have reported several families with an autosomal dominant sensory neuropathy associated with hearing loss and later dementia caused by mutations in DNMT1. See DNMT1-Related Dementia, Deafness, and Sensory Neuropathy.
  • Sumner et al [2013] have reported an autosomal dominant spinal muscular atrophy with calf predominance (but also including triceps and hand weakness) associated with a missense mutation (p.Cys206Arg) in FBX038. Onset ranged from age 13 to 48 years, severity ranged from mild and severe and nerve conductions showed reduced motor evoked amplitudes.
  • Klein et al [2014] reported a missense mutation (p.Arg317Cys) in DCAF8 responsible for a specific variety of autosomal dominant CMT2/HMSN2 in a German family with infrequent giant axons seen on nerve biopsy and mild cardiomyopathy. This mutation results in decreased DDb1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation.

An intermediate form of CMT inherited in an autosomal dominant manner has been described; affected individuals have a relatively typical CMT phenotype with nerve conduction velocities that overlap those observed in CMT1 (demyelinating form) and CMT2 (axonal form). Motor NCVs in these families usually range between 25 and 50 m/sec. At least three chromosomal loci (1p, 10q, and 19p) for this intermediate form have been identified by linkage analysis [Kennerson et al 2001, Verhoeven et al 2001]. Mutations in YARS and DNM2 may cause this syndrome.

Mitochondrial causes. Mitochondrial abnormalities are known to sometimes be associated with peripheral neuropathy. Mutations in the nuclear gene MFN2 produce abnormal mitochondrial fusion/fission and resultant neuropathy (CMT2A). Mutations in the mitochondrial genome may also be associated with neuropathy, for example in NARP. Pitceathly et al [2012] have reported an axonal predominantly motor neuropathy associated with the m.9185T>C mutation in MT-ATP6.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to the most common type of CMT2 (CMT2A2), go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2), the following evaluations are recommended:

  • Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
  • Nerve conduction velocity (NCV)
  • Complete family history
  • Medical genetics consultation

Treatment of Manifestations

Treatment is symptomatic. 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].

The following may be indicated:

  • Special shoes, including those with good ankle support
  • Ankle/foot orthoses (AFO) to correct foot drop and aid walking
  • Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000]
  • Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
  • Treatment of sleep apnea or restless legs [Aboussouan et al 2007]

Exercise is encouraged within the individual's capability and many individuals remain physically active.

Pain and depression should be treated symptomatically [Gemignani et al 2004, Padua et al 2006].

Prevention of Secondary Complications

Daily heel cord-stretching exercises are helpful in preventing Achilles' tendon shortening.

Surveillance

Gait and condition of feet should be monitored to determine need for bracing, special shoes, or surgery.

Agents/Circumstances to Avoid

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

Medications which are toxic or potentially toxic to persons with CMT comprise a range of risks including:

  • Definite high risk. Vinca alkaloids (Vincristine)
    Note: This category should be avoided by all persons with CMT, including those who are asymptomatic.
  • Other potential risk levels. See Table 4. For more information, click here (pdf).

Table 4. Medications Potentially Toxic to Persons with CMT

Moderate to Significant Risk 1
- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava)
- Metronidazole/misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or vitamin B12 deficiency)
- Perhexiline (not used in US)
- 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 testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMT. About 50% of women with CMT describe increased weakness during pregnancy that usually resolves post partum [Rudnik-Schoneborn et al 1993]. Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] have described the obstetric approach to women with mild and severe forms of CMT.

A recent German study reviewed 63 pregnancies in 33 individuals with CMT [Awater et al 2012] and found no increase in the frequency of Cesarean sections, forceps deliveries, premature births, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet.

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

CMT2B1, CMT2B2, and CMT2H/2K are inherited in an autosomal recessive manner; all other subtypes of Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) are inherited in an autosomal dominant manner.

CMT2P has been reported to be inherited in an autosomal recessive manner in one family and in an autosomal dominant manner in one family.

Risk to Family Members — Autosomal Dominant CMT2

Parents of a proband

Note: Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband. The risk to sibs depends on the genetic status of the proband's parents.

Offspring of a proband. Every child of an individual with autosomal dominant CMT2 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a disease-causing mutation, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive CMT2

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

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

Offspring of a proband. The offspring of an individual with autosomal recessive CMT2 are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Carrier testing for at-risk family members for autosomal recessive forms of CMT2 is possible if the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made 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 or at risk.

Testing of at-risk asymptomatic adults. Asymptomatic adults at risk of having inherited a pathogenic variant associated with autosomal dominant CMT2 may wish to pursue further clinical evaluation and NCV testing. No treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.

Testing of at-risk asymptomatic individuals during childhood. Testing of at-risk asymptomatic individuals who are younger than age 18 years is not appropriate. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like CMT2) do not affect intellect or life span are not common. Differences in perspectives may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) of CMT2E [Sharapova et al 2004] and CMT2F [Lee et al 2013b] has been reported. Preimplantation genetic diagnosis of other CMT2 subtypes may be an option for some families in which the pathogenic variant(s) have been identified.

Resources

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

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

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

Table A. Charcot-Marie-Tooth Neuropathy Type 2: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CMT2NAARS16q22​.1Alanyl-tRNA synthetase, cytoplasmicAARS @ LOVDAARS
CMT2A2MFN21p36​.22Mitofusin-2MFN2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MFN2
MFN2
CMT2BRAB7A3q21​.3Ras-related protein Rab-7aRAB7A homepage - Leiden Muscular Dystrophy pages
IPN Mutations, RAB7A
RAB7A
CMT2B1LMNA1q22Prelamin-A​/CHuman Intermediate Filament Database LMNA (lamin C1)
Human Intermediate Filament Database LMNA (lamin A)
Human Intermediate Filament Database LMNA (lamin C2)
LMNA homepage - Leiden Muscular Dystrophy pages
IPN Mutations, LMNA
The UMD-LMNA mutations database
LMNA
CMT2B2MED2519q13​.33Mediator of RNA polymerase II transcription subunit 25MED25 homepage - Mendelian genesMED25
CMT2CTRPV412q24​.11Transient receptor potential cation channel subfamily V member 4TRPV4 homepage - Mendelian genesTRPV4
CMT2DGARS7p14​.3Glycine--tRNA ligasealsod/GARS genetic mutations
GARS homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GARS
GARS
CMT2ENEFL8p21​.2Neurofilament light polypeptideHuman Intermediate Filament Database NEFL
NEFL homepage - Leiden Muscular Dystrophy pages
IPN Mutations, NEFL
NEFL
CMT2FHSPB17q11​.23Heat shock protein beta-1HSPB1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, HSPB1
HSPB1
CMT2GUnknown12q12-q13​.3Unknown
CMT2H/2KGDAP18q21​.11Ganglioside-induced differentiation-associated protein 1GDAP1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GAPD1
GDAP1
CMT2IMPZ1q23​.3Myelin P0 proteinMPZ homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MPZ
MPZ
CMT2JMPZ1q23​.3Myelin P0 proteinMPZ homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MPZ
MPZ
CMT2LHSPB812q24​.23Heat shock protein beta-8HSPB8 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, HSPB8
HSPB8
CMT2ODYNC1H114q32​.31Cytoplasmic dynein 1 heavy chain 1alsod/DYNC1H1 genetic mutationsDYNC1H1
CMT2PLRSAM19q33​.3E3 ubiquitin-protein ligase LRSAM1 LRSAM1

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

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

150330LAMIN A/C; LMNA
159440MYELIN PROTEIN ZERO; MPZ
162280NEUROFILAMENT PROTEIN, LIGHT POLYPEPTIDE; NEFL
600112DYNEIN, CYTOPLASMIC 1, HEAVY CHAIN 1; DYNC1H1
600287GLYCYL-tRNA SYNTHETASE; GARS
600882CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B
601065ALANYL-tRNA SYNTHETASE; AARS
601472CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D; CMT2D
602195HEAT-SHOCK 27-KD PROTEIN 1; HSPB1
602298RAS-ASSOCIATED PROTEIN RAB7; RAB7
605427TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4
605588CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1; CMT2B1
605589CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2; CMT2B2
606071HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C
606595CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F; CMT2F
606598GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1
607677CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2I; CMT2I
607684CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E; CMT2E
607731CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2H; CMT2H
607736CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2J; CMT2J
607831CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2K; CMT2K
608014HEAT-SHOCK 22-KD PROTEIN 8; HSPB8
608507MITOFUSIN 2; MFN2
608591CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2G; CMT2G
608673CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L; CMT2L
609260CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2
610197MEDIATOR COMPLEX SUBUNIT 25; MED25
610933LEUCINE-RICH REPEAT- AND STERILE ALPHA MOTIF-CONTAINING 1; LRSAM1
613287CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N; CMT2N
614228CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2O; CMT2O
614436CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P; CMT2P

Molecular Genetic Pathogenesis

The relationship of myelin and axon pathology to the pathogenesis of CMT is discussed in detail in several reviews [Krajewski et al 2000, Berger et al 2002, Maier et al 2002, Züchner & Vance 2006a, Züchner & Vance 2006b]. Rossor et al [2013] show the molecular and anatomic relationships of the various genes and proteins associated with CMT; see Figure 1.

For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

KIF1B

Gene structure. KIF1B comprises 47 exons and 167.13 kb of DNA.

Pathogenic allelic variants. A p.Gln98Leu mutation was reported in a single family [Zhao et al 2001]. See also Table A.

Table 5. Selected KIF1B Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.293A>Tp.Gln98LeuNM_015074​.3
NP_055889​.2

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

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

Normal gene product. Kinesin-like protein KIF1B is involved in axonal transport of synaptic vesicle precursors [Zhao et al 2001]. The kinesin superfamily of proteins is essential for intracellular transport along microtubules.

Abnormal gene product. There may be a defect in the transport of synaptic vesicles.

MFN2

Gene structure. MFN2 has 19 exons with a 2274-bp open reading frame.

Pathogenic allelic variants. Züchner et al [2004b] and Verhoeven et al [2006] have reported more than 25 missense mutations in MFN2. See also Table A.

Normal gene product. Mitofusin-2, encoded by MFN2, is involved in mitochondrial network architecture and mediates mitochondrial fusion.

Abnormal gene product. Mutations in MFN2 may disrupt the mitochondrial fusion-fission balance in peripheral nerve. Diminished axonal mitochondrial transport has been described [Baloh et al 2007].

RAB7A

Gene structure. RAB7A has six exons and 87.9 kb of DNA.

Pathogenic allelic variants. See Table A.

Normal gene product. Ras-related protein Rab-7a belongs to the RAB family of Ras-related GTPases essential for the regulation of intracellular membrane trafficking. Rab-7a is involved in transport between late endosomes and lysosomes. RAB-interacting lysosomal protein (RILP) induces the recruitment of dynein-dynactin motors and regulates transport toward the minus-end of microtubules [Verhoeven et al 2003].

Abnormal gene product. Abnormal Rab-7a may cause malfunction of lysosomes.

LMNA

Gene structure. LMNA has 12 exons spread over 24 kb of genomic DNA.

Pathogenic allelic variants. The most common pathogenic variant found in individuals with CMT2B1 is p.Arg298Cys. See also Table A.

Table 6. Selected LMNA Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Benignc.1908C>Tp.= 1NM_170707​.2
NP_733821​.1
Pathogenicc.398G>Tp.Arg133Leu
c.892C>Tp.Arg298Cys
c.1411C>Tp.Arg471Cys
c.1579C>Tp.Arg527Cys

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

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

1. p.= signifies that protein has been analyzed but no amino acid change is expected.

Normal gene product. Lamins are the principal component of the nuclear lamina, a major portion of the nuclear envelope. Two A-type lamins exist: A and C. Lamins play a role in DNA replication, chromatin organization, spatial arrangement of nuclear pore complexes, nuclear growth, mechanical stabilization of the nucleus, and anchorage of the nuclear envelope protein.

Abnormal gene product. Position 29 is located in the lamin-A/C rod domain. The manner in which disruption of this domain adversely affects peripheral nerve function is unknown. Other LMNA mutations are associated with a wide variety of disorders (see Genetically Related Disorders).

MED25

Gene structure. MED25 has 18 exons.

Pathogenic allelic variants. One pathogenic variant has been described in an extended Costa Rican family with autosomal recessively inherited CMT neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. Affected individuals were homozygous for p.Ala335Val [Leal et al 2009].

Table 7. Selected MED25 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.1004C>Tp.Ala335ValNM_030973​.2
NP_112235​.2

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

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

Normal gene product. MED25 encodes a 747-amino acid protein designated the mediator complex subunit 25 protein (reference sequence NM_030973.2). This protein is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes. Its precise function in transcriptional regulation is unknown.

Abnormal gene product. The p.Ala335Val substitution is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins.

TRPV4

Gene structure. TRPV4 has 16 exons; exon 1 of NM_021625.3 is non-coding.

Pathogenic allelic variants. The mutations in Table 8 have been associated with CMT2C.

Table 8. Selected TRPV4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.805C>Tp.Arg269CysNM_021625​.3
NP_067638​.3
c.806G>Ap.Arg269His
c.943C>Tp.Arg315Trp
c.946C>Tp.Arg316Cys

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

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

Normal gene product. TRPV is a vanilloid receptor-related transient receptor potential channel which plays an important role in neural signal. The protein is composed of a cytosolic N-terminal region and six transmembrane domains, including the pore region and an intracellular C-terminal tail. The N-terminal region contains the ankyrin repeat domain (ARD).

Abnormal gene product. Landouré et al [2010] demonstrated cellular toxicity and increased constitutive and activated channel currents in TRPV4-transected cells. Deng et al [2010] showed increased calcium channel activity resulting from the two mutations found in two families with CMT2C. The effect of mutations on molecular functions like oligomerization, surface expression and ubiquitination are reviewed by Verma et al [2010].

GARS

Gene structure. GARS is a 40-kb gene with 17 exons.

Pathogenic allelic variants. See Table A.

Normal gene product. Glycyl-tRNA synthetase ligates amino acids to their cognate tRNA.

Abnormal gene product. The missense mutations in this gene may produce a loss of function that allows the incorporation of the wrong amino acid in the place of glycine [Motley et al 2010].

NEFL

Gene structure. NEFL contains four coding exons; the 5' UTRs are highly conserved.

Pathogenic allelic variants. One family with CMT2E/1F has a mutation in exon 1 of NEFL [Mersiyanova et al 2000] and another family has a deletion/insertion mutation in exon 1 (c.22_23delCCinsAG) [De Jonghe et al 2001]. See also Table A.

Table 9. Selected NEFL Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.22_23delCCinsAGp.Pro8ArgNM_006158​.1
NP_006149​.2

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

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

Normal gene product. Neurofilament light polypeptide, the protein encoded by NEFL, contains 543 amino acids with a head, rod, and tail domain. Neurofilaments form the cytoskeletal component of myelinated axons.

Abnormal gene product. Knockout mice lacking neurofilaments have diminished axon caliber and delayed regeneration of myelinated axons following crush injury. A mouse mutation in Nefl has massive degeneration of spinal motor neurons and abnormal neurofilament accumulation with severe neurogenic skeletal muscle atrophy. Defects in transport and assembly of neurofilaments have been reported [Perez-Olle et al 2004].

HSPB1 (HSP27)

Gene structure. HSPB1 contains three exons with a central HSP20-α-crystallin domain.

Pathogenic allelic variants. See Table A.

Normal gene product. The heat shock protein beta-1 (also referred to as heat-shock protein 27) has many possible functions including antiapoptotic and cytoprotective properties, inhibition of caspase activation, prevention of aggresome formation, and involvement in the neurofilament network.

Abnormal gene product. Mutations in HSPB1 result in altered neurofilament assembly [Evgrafov et al 2004].

MPZ

Gene structure. MPZ spans approximately 7 kb and contains six exons.

Pathogenic allelic variants. More than 56 point mutations in MPZ have been reported [Nelis et al 1999]. More than 70% of the mutations are localized in exons 2 and 3 of MPZ coding for the extracellular domain, indicating the functional importance of this domain (see also Table A).

Table 10. Selected MPZ Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.254A>Tp.Asp85Val
(p.Asp75Val)
NM_000530​.5
NP_000521​.1
c.401C>Tp.Thr134Met
(p.Thr124Met)

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

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

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

Normal gene product. Myelin P0 protein is a major structural component of peripheral myelin representing about 50% of peripheral myelin protein by weight and about 7% of Schwann cell message. It is a homophilic adhesion molecule of the immunoglobulin family that plays an important role in myelin compaction. It has a single transmembrane domain, a large extracellular domain, and a smaller intracellular domain.

Abnormal gene product. Different mutations affect all portions of the protein and may alter myelin adhesion. Either demyelinating or axonal phenotypes can result.

GDAP1

Gene structure. GDAP1 has six exons, 13.9 kb of DNA, and a 1007-nucleotide open reading frame.

Pathogenic allelic variants. See also Table A.

Table 11. Selected GDAP1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.358C>Tp.Arg120TrpNM_018972​.2
NP_061845​.2

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

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

Normal gene product. Ganglioside-induced differentiation-associated protein-1 [Baxter et al 2002]

Abnormal gene product. It is speculated that mutations may prevent the correct catalyzing S conjugation of reduced GCH, resulting in progressive attrition of both axons and Schwann cells.

HSPB8 (HSP22)

Gene structure. HSPB8 has three exons and spans about 16 kb.

Pathogenic allelic variants. Three mutations have been reported. See Table 12 [Irobi et al 2004b, Tang et al 2005].

Table 12. Selected HSPB8 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.423G>T p.Lys141AsnNM_014365​.2
NP_055180​.1
c.423G>Cp.Lys141Asn
c.421A>Gp.Lys141Glu

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

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

Normal gene product. HSPB8 (also called HSP22) is a phosphor protein that interacts with HSPB1.

Abnormal gene product. Mutant HSPB8 proteins interact with HSPB1 and form aggregates that may lead to dysfunctional axonal transport and dysregulation of the cytoskeleton [Irobi et al 2004b].

AARS

Gene structure. AARS has 21 exons and is located on chromosome 16.

Pathogenic allelic variants. Two mutations have been associated with CMT (p.Arg329His and p.Glu778Ala). See Table 13. The mutation p.Asn71Tyr (c.211A>T) may also be pathogenic.

Table 13. Selected AARS Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.986G>Ap.Arg329HisNM_001605​.2
NP_001596​.2
c.2333A>Cp.Glu778Ala

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

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

Normal gene product. Alanyl-tRNA synthetase attaches alanine to tRNA molecules in cytoplasm and mitochondria completing the first step in protein translation.

Abnormal gene product. Functional studies suggest these are loss of function mutations [McLaughlin et al 2012].

DYNC1H1

Pathogenic allelic variants. One human mutation has been described (p.His306Arg) by Weedon et al [2011]. See Table 14.

Table 14. Selected DYNC1H1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.917A>Gp.His306ArgNM_001376​.4 (MIM600112)

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

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

Normal gene product. 4,644-amino acid protein. DYNC1H1 is a subunit of cytoplasmic dynein, the primary motor protein producing retrograde axonal transport in neurons.

Abnormal gene product. Presumably the abnormal protein produces defective retrograde axonal transport in peripheral nerves.

LRSAM1

Pathogenic allelic variants. A single autosomal dominant and a single autosomal recessive mutation have been described. See Table 15.

Table 15. Selected LRSAM1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2121_2122 insGCp.Leu708ArgfsTer28--
AG>AA exon 24Intronic splice site

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

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

Normal gene product. A ubiquitin ligase (E3) involved with sorting ubiquitinylated cytoplasmic cargo (TSG101); 702-amino acid 70-kd protein

Abnormal gene product. Disturbs sorting of ubiquitinylated cargo in neuronal cytoplasm.

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 5-1-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 5-1-14.

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Chapter Notes

Revision History

  • 3 April 2014 (tb) Revision: addition of DCAF8 to Differential Diagnosis [Klein et al 2014]
  • 20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic diagnosis
  • 30 January 2014 (tb) Revision: Sumner et al [2013]; edits to Testing Strategy
  • 14 November 2013 (tb) Revision: figure added to Prevalence and Molecular Genetics [Rossor et al 2013]
  • 11 July 2013 (tb) Revision: additions to Prevalence and Differential Diagnosis
  • 3 January 2013 (cd) Revision: sequence analysis of select exons of LRSAM1 available clinically
  • 13 December 2012 (tb) Revision: mutations in DHTKD1 identified as causative of a form of CMT2 [Xu et al 2012]
  • 13 September 2012 (tb) Revision: addition of Nicolaou et al [2012], Ishiura et al [2012], Pitceathly et al [2012]
  • 30 August 2012 (cd) Revision: sequence analysis for MED25 and DYNC1H1 available clinically
  • 5 July 2012 (me) Comprehensive update posted live
  • 9 February 2012 (tb) Revision: mutations in DYNC1H1 reported to be associated with CMT2O; mutation in LRSAM1 associated with CMT2P
  • 22 December 2011 (tb) Revision: mutations in AARS cause CMT2N.
  • 15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT
  • 18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in MED25 associated with CMT2B2
  • 1 March 2011 (cd) Revision: edits to Testing Strategy
  • 27 January 2011 (cd) Revision: testing available clinically for CMT2C
  • 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
  • 11 March 2010 (me) Comprehensive update posted live
  • 7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available
  • 16 August 2007 (me) Comprehensive update posted to live Web site
  • 30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D
  • 30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available
  • 21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V
  • 14 June 2005 (tb) Revision: CMT2K added
  • 4 May 2005 (me) Comprehensive update posted to live Web site
  • 6 December 2004 (tb) Revision: testing
  • 9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available
  • 9 August 2004 (tb,cd) Revision: CMT2B1
  • 21 June 2004 (tb) Revision: CMT2F
  • 10 May 2004 (tb) Author revisions
  • 1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E
  • 7 April 2003 (me) Comprehensive update posted to live Web site
  • 12 September 2001 (tb) Author revisions
  • 24 July 2001 (tb) Author revisions
  • 27 June 2001 (tb) Author revisions
  • 19 June 2001 (tb) Revision: CMT2A gene found
  • 23 March 2001 (tb) Author revisions
  • 16 January 2001 (tb) Author revisions
  • 25 August 2000 (me) Comprehensive update posted to live Web site
  • 15 June 2000 (tb) Author revisions
  • 15 May 2000 (tb) Author revisions
  • 3 February 2000 (tb) Author revisions
  • 12 October 1998 (tb) Author revisions
  • 24 September 1998 (pb) Review posted to live Web site
  • April 1996 (tb) Original submission
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