Autosomal dominant Charcot-Marie-Tooth disease type 2M
General Information (adopted from Orphanet):
Synonyms, Signs:
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2M, INCLUDED
CMT2M, INCLUDED
CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2M, INCLUDED
DI-CMTB
CMTDI1 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2M, INCLUDED
CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE B, WITH NEUTROPENIA, INCLUDED
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B, WITH NEUTROPENIA, INCLUDED
CMTDIB
CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE B
CMT2M
Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms.
- Classification ... Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. - Classification CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by Salisachs (1974) and Davis et al. (1978). Davis et al. (1978) proposed that this form be designated 'intermediate' CMT. Claeys et al. (2009) stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values). - Genetic Heterogeneity of Autosomal Dominant Intermediat
Kennerson et al. (2001) described a form of CMT that they referred to as 'dominant intermediate CMT.' They used the term 'intermediate conduction velocity' to describe CMT families with nerve conduction velocities, in different affected individuals, that overlap ... Kennerson et al. (2001) described a form of CMT that they referred to as 'dominant intermediate CMT.' They used the term 'intermediate conduction velocity' to describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between CMT1 and CMT2. Kennerson et al. (2001) reported a large Australian family in which affected members had nerve conduction velocities ranging from 24 to 54 m/s. The sural nerve biopsy in this family showed axonal degeneration, loss of large diameter fibers, rare segmental demyelination, and remyelination with onion bulb formation. Claeys et al. (2009) reviewed the phenotypic spectrum of CMT in 37 patients from 6 families with dynamin-2 mutations. Several of the families had previously been reported (see, e.g., Kennerson et al., 2001). The mean age at onset was 16 years (range, 2-50). Patients presented with a classic CMT phenotype of distal lower limb weakness and atrophy resulting in gait abnormalities and frequent falls. Electrophysiologic studies showed intermediate or axonal motor median nerve conduction velocities ranging from 26 m/s to 54 m/s; variations occurred in the same family. Sural nerve biopsy in 1 family showed diffuse loss of myelinated fibers, regenerating axons, and focal myelin thickenings without segmental demyelination. Two families had associated neutropenia, and 1 family developed early-onset cataracts. - Axonal Charcot-Marie-Tooth Disease 2M Fabrizi et al. (2007) reported 2 unrelated families with CMT due to heterozygous mutations in the DNM2 gene (602378.0008; 602378.0009, respectively). The proband of 1 family had pes cavus, mildly ataxic gait, weakness of foot dorsiflexion, peripheral sensory neuropathy, and mild wasting of the intrinsic hand muscles. Her son had painful paresthesias, pes cavus, clawed toes, wasting of the peroneal muscles, steppage gait with sensory ataxia, and preservation of intrinsic hand muscles. Median nerve conduction velocities were normal, consistent with an axonal form of CMT. Sural nerve biopsy showed loss of large diameter fibers and rare onion bulb formations. Overall, the histology was consistent with an axonal neuropathy without detectable demyelination. Fabrizi et al. (2007) noted that the phenotype in this family was milder than that reported in other families with DNM2 mutations, and emphasized that axonal changes without demyelinating changes can be present. Gallardo et al. (2008) reported a mother and her 2 adult daughters with axonal Charcot-Marie-Tooth disease (CMT2M). The patients were ages 55, 32, and 23, and motor nerve conduction velocities were 33, 46, and 50 m/s, respectively. All had progressive gait unsteadiness and foot deformities, including pes cavus and toe clawing, in the first decade of life. All had distal muscle weakness and atrophy of the lower limbs, and the mother also had hand weakness and atrophy. Ankle reflexes were absent in all 3, and all had hypoesthesia of the lower limbs. MRI studies showed fatty infiltration of the calf muscles, particularly in the anterior compartment. The fatty infiltration increased distally and was massive in the foot musculature. Muscle edema was also present in affected muscles. In a follow-up of the family reported by Gallardo et al. (2008), Claeys et al. (2009) concluded that the phenotype was consistent with axonal CMT.
Zuchner et al. (2005) presented evidence that the form of dominant intermediate CMT that maps to 19p13.2-p12 is caused by mutations in the gene encoding dynamin-2 (DNM2; 602378). They refined the locus associated with DI-CMTB to 4.2 Mb ... Zuchner et al. (2005) presented evidence that the form of dominant intermediate CMT that maps to 19p13.2-p12 is caused by mutations in the gene encoding dynamin-2 (DNM2; 602378). They refined the locus associated with DI-CMTB to 4.2 Mb and found unique mutations in DNM2 in the American family described by Speer et al. (2002), the Australian family of Kennerson et al. (2001) and Zhu et al. (2003), and in an additional multigenerational Belgian family. In the Australian and Belgian pedigrees, which carried 2 different mutations affecting the same amino acid, lys558 (602378.0002, 602378.0003), CMT cosegregated with neutropenia, which had not previously been associated with CMT neuropathies. In a mother and her 2 daughters with axonal CMT, Gallardo et al. (2008) identified a heterozygous mutation in the DNM2 gene (G358R; 602378.0012).
DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) is a so-called “dominant intermediate form” of CMT neuropathy because it is inherited in an autosomal dominant manner and it is “intermediate” between a demyelinating and axonal neuropathy using strict electrophysiologic criteria for nerve conduction velocities (NCVs). In intermediate CMT median motor NCVs are between 25 and 45 m/s [Davis et al 1978, Nicholson & Myers 2006]. ...
DiagnosisClinical Diagnosis DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) is a so-called “dominant intermediate form” of CMT neuropathy because it is inherited in an autosomal dominant manner and it is “intermediate” between a demyelinating and axonal neuropathy using strict electrophysiologic criteria for nerve conduction velocities (NCVs). In intermediate CMT median motor NCVs are between 25 and 45 m/s [Davis et al 1978, Nicholson & Myers 2006]. Classic CMT symptoms of sensory and motor deficiencies at the lower legs dominate the clinical picture: sensory deficits, depressed ankle reflex, atrophy, and foot deformities. The diagnosis can only be established with molecular genetic testing of DNM2.Molecular Genetic TestingGene. DNM2 is the only gene associated with DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB).Clinical testingSequence analysis detects a mutation in nearly 100% of individuals with DI-CMTB.Table 1. Summary of Molecular Genetic Testing Used in DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityDNM2Sequence analysisSequence variants 2Nearly 100%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband, the identification of a disease-causing mutation in DNM2 is necessary. In a person with a CMT phenotype and very slow NCV (<30m/s), perform molecular genetic testing of PMP22 first to determine if a PMP22 duplication, the most common cause of this demyelinating phenotype, is present. In a person with a CMT phenotype and intermediate to normal NCV, perform molecular genetic testing of the MPZ, GJB1 (encoding the protein connexin 32), and MFN2 genes first because mutation of one of these genes is a common cause of this phenotype. In a person with a CMT phenotype and NCV between 30 and 45 m/s in whom testing for the above genes has not identified a disease-causing mutation, molecular genetic testing of DNM2 is appropriate. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders Autosomal dominant centronuclear myopathy (DNM2-related CNM) is also associated with mutations in DNM2 [Bitoun et al 2005]. DNM2-related CNM usually presents with neonatal hypotonia, weak suck, poor feeding and progressive muscle weakness with respiratory problems [Jungbluth et al 2010, Melberg et al 2010].Some individuals with CNM have clinical findings that overlap with DI-CMTB [Fischer et al 2006, Bitoun et al 2008, Susman et al 2010]. The findings shared between DI-CMTB and CNM are muscle weakness and sometimes cataract. CNM does not have peripheral nerve involvement and often has proximal muscle weakness that is not seen in DI-CMTB.
DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) has a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy phenotype that often includes pes cavus foot deformity, depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss. ...
Natural History DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) has a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy phenotype that often includes pes cavus foot deformity, depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss. Mean age at onset is 16 years; onset range is from age two to 50 years. Some persons require AFO braces or other walking aids. Three per cent of affected individuals become wheelchair bound; one person in the Claeys et al [2009] study required a wheelchair at age 61 years.Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years). Electrophysiologic studies indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values. Pure axonal CMT has been described.Sural nerve biopsy has shown diffuse loss of large myelinated fibers, clusters of regenerating myelinated axons, and fibers with focal myelin thickenings [Kennerson et al 2001, Claeys et al 2009].
Strong genotype-phenotype correlations have not been reported....
Genotype-Phenotype Correlations Strong genotype-phenotype correlations have not been reported.The majority of DNM2 mutations appear to be in the domain encoding homology to pleckstrin [Züchner et al 2005, Fabrizi et al 2007]; however, exceptions have been identified [Claeys et al 2009, Susman et al 2010].
The other two forms of intermediate CMT are DI-CMTA (linked to 10q24) [Verhoeven et al 2001] and DI-CMTC, caused by mutations in YARS (formerly TyrRS) (linked to 1p35.5) [Jordanova et al 2006]....
Differential DiagnosisThe other two forms of intermediate CMT are DI-CMTA (linked to 10q24) [Verhoeven et al 2001] and DI-CMTC, caused by mutations in YARS (formerly TyrRS) (linked to 1p35.5) [Jordanova et al 2006].It is usually not possible to differentiate between DI-CMTB, other intermediate forms of CMT, and most CMT2 types based on clinical findings [Nicholson & Meyers 2006], unless cataract and/or neutropenia, occasional findings in DI-CMTB, are present.See CMT Overview, particularly to exclude potentially treatable causes of acquired neuropathy.
To establish the extent of disease in an individual diagnosed with DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB), the following evaluations are recommended:Neurologic examinationElectrophysiologic studies to help differentiate from demyelinating forms of CMT and to establish a baseline for further monitoring of disease progressionComplete blood count (CBC) with absolute neutrophil count (ANC) to evaluate for neutropeniaOphthalmologic examination for cataractTreatment of ManifestationsTreatment of DI-CMTB is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, orthopedic surgeons, and physical and occupational therapists. Treatment may include: Ankle/foot orthoses Orthopedic surgery Forearm crutches or canes; wheelchairs Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents (NSAIDs) Career and employment counseling SurveillanceSurveillance includes regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.Agents/Circumstances to AvoidMedications which are toxic or potentially toxic to persons with CMT comprise a range of risks including:Definite high risk: Vinca alkaloids (vincristine)This category should be avoided by all persons with CMT, including those who are asymptomatic.Other potential risk levels: See Table 2. For more information, click here (pdf).Table 2. Medications Potentially Toxic to Persons with CMTView in own windowModerate to Significant Risk 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 InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
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. DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDI-CMTBDNM219p13.2Dynamin-2IPN Mutations, DNM2 DNM2 homepage - Leiden Muscular Dystrophy pagesDNM2Data 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 DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy (View All in OMIM) View in own window 602378DYNAMIN 2; DNM2 606482CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B; CMTDIBNormal allelic variants. DNM2 has several isoforms, the longest transcript is isoform 1 (NM_001005360.1), which has 22 exons. See Entrez Gene for a description of isoforms.Pathologic allelic variants. Missense mutations and small deletions in the coding region have been described.Normal gene product. Isoform 1 encodes a dynamin 2 protein of 870 amino acid residues (NP_001005360.1). Abnormal gene product. The identification of small deletions suggests that haploinsufficiency is the cause of the disorder.