Disease characteristics. Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity.
Diagnosis/testing. The diagnosis of CMT4 subtypes is based on clinical, pathologic, and genetic criteria. The genes associated with eight CMT4 subtypes have been identified: GDAP1 (CMT4A), MTMR2 (CMT4B1), CMT4B2 (CMT4B2), SH3TC2 (or KIAA1985) (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FGD4 (CMT4H), and FIG1 (CMT4J). Molecular genetic testing for most of these genes is available on a clinical basis.
Management. Treatment of manifestations: Treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; symptomatic treatment of pain, depression, sleep apnea, restless leg 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 (makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage. Other: career and employment counseling.
Genetic counseling. The CMT4 subtypes are inherited in an autosomal recessive manner. Parents of an affected individual are obligate carriers of the CMT4-related gene mutation present in their family. 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. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutations in an affected family member have been identified.
Charcot-Marie-Tooth neuropathy type 4 (CMT4) is diagnosed in individuals with the following:
Progressive motor and sensory neuropathy
Nerve conduction velocities (NCVs) that are usually slow (<40 m/s)
A family history consistent with autosomal recessive inheritance (i.e., parents not affected unless multigeneration consanguinity exists)
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes
CMT4A. GDAP1 [Palau et al 2001, Baxter et al 2002, Cuesta et al 2002]. About 25% of autosomal recessive CMT is attributable to mutations in GDAP1 [Zuchner & Vance 2006].
CMT4B1. MTMR2 [Bolino et al 2000]
CMT4B2. CMT4B2 (SBF2/MTMR13) [Azzedine et al 2003, Senderek et al 2003c]
CMT4C. SH3TC2 (KIAA1985) [LeGuern et al 1996, Senderek et al 2003b]
CMT4D. NDRG1 [Kalaydjieva et al 2000]
CMT4E. EGR2 [Warner et al 1998, Warner et al 1999, Boerkoel et al 2001a]
CMT4F. PRX [Boerkoel et al 2001b]
CMT4H. FGD4 [Delague et al 2007]
CMT4J. FIG4 [Chow et al 2007]
Other loci
Leal et al [2001] reported an axonal neuropathy of late onset (mean age 34 years n a Costa Rican family linked to 19q13.3. Berghoff et al [2004] further characterized this family and Rautenstrauss et al [2005] preliminarily reported a mutation in the MED25 gene.
Barhoumi et al [2001] reported a Tunisian family with severe CMT linked to 8q21.3. (Some classifications consider this CMT2H.)
Rogers et al [2000] and Thomas et al [2001] reported a severe disabling form of peripheral neuropathy with prominent sensory loss and moderately reduced motor NCVs in Balkan (Russe) Gypsies linked to 10q22. The disease is less severe than CMT4D occurring in the Lom Gypsies [Guergueltcheva et al 2006].
Clinical testing
Sequence analysis. Sequence analysis of the genes associated with CMT4A, CMT4B1, CMT4B2, CMT4C, CMT4D, CMT4E, CMT4F, and CMT4H is available on a clinical basis.
Targeted mutation analysis. Testing for the p.Arg148X mutation in NDRG1 (CMT4D) is available on a clinical basis.
Research testing. Molecular genetic testing of the genes associated with CMT4H and CMT4J is available on a research basis only.
Table 1 summarizes molecular genetic testing for this disorder.
Locus Name / Subtype | Test Method | Mutations Detected | Proportion of CMT4 Attributed to Mutations in This Gene | Mutation Detection Frequency 1 | Test Availability |
---|---|---|---|---|---|
CMT4A | Sequence analysis | GDAP1 sequence variants | ~25% | 100% | Clinical |
CMT4B1 | MTMR2 sequence variants | Rare | Clinical | ||
CMT4B2 | CMT4B2 (SBF2/MTMR13) sequence variants | Clinical | |||
CMT4C | SH3TC2 (KIAA1985) sequence variants | Clinical | |||
CMT4D | NDRG1 sequence variants | Unknown | Clinical | ||
Targeted mutation analysis | p.Arg148X in NDRG1 | ||||
CMT4E | Sequence analysis | EGR2 sequence variants | 100% | Clinical | |
CMT4F | PRX sequence variants | Clinical | |||
CMT4H | FGD4 sequence variants | Clinical | |||
CMT4J | Direct DNA | Mutations in FIG4 | Unknown | Research only 2 |
1. Proportion of affected individuals with a mutation(s) as classified by CMT4 subtype; each subtype is identified based on detection of a mutation in the causative gene; hence, the mutation detection frequency is 100%.
2. No laboratories offering clinical molecular genetic testing for these subtypes are listed in the GeneTests Laboratory Directory. However, clinical confirmation of mutations identified in research laboratories may be available for families in which a disease-causing mutation has been identified in a research laboratory. For laboratories offering such testing, see .
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirming the diagnosis in a proband. In families in which an autosomal recessive neuropathy is suspected, it is reasonable to test first for mutations in GDAP1 (CMT4A) because it is most common; CMT4E (EGR2) is perhaps the next most common. All others are rare.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
GDAP1. CMT4A is the only phenotype associated with GDAP1. Mutations in GDAP1 have occasionally been associated with autosomal dominant inheritance (CMT2K) [Claramunt et al 2005].
MTMR2. CMT4B1 is the only phenotype associated with MTMR2.
CMT4B2 (SBF2/MTMR13). CMT4B2 is the only phenotype associated with CMT4B2 (SBF2/MTMR13).
SH3TC2 (KIAA1985). CMT4C is the only phenotype associated with SH3TC2 (KIAA1985).
NDRG1. CMT4D is the only phenotype associated with NDRG1.
EGR2 (CMT4E). Mutations in EGR2 are also associated with autosomal dominant CMT1D [Warner et al 1998, Warner et al 1999, Boerkoel et al 2001a].
PRX. CMT4F is the only phenotype associated with PRX.
The subtypes of Charcot-Marie-Tooth neuropathy type 4 (CMT4) are based on clinical characteristics, ethnic background, neuropathologic findings, and gene or chromosomal locus. Individuals with CMT4 usually have the clinical characteristics of the CMT phenotype, including distal muscle weakness and atrophy, sensory loss, and, often, pes cavus foot deformity. (See CMT Overview for more details.) Some subtypes have specific clinical characteristics such as the sensorineural deafness associated with CMT4D. Both axonal and demyelinating neuropathies are included in CMT4.
CMT4A was first identified in families in Tunisia [Othmane et al 1995]. Typically, delayed motor development is noted in the second year of life. Distal muscle weakness and atrophy of feet progress to involve the proximal muscles by the end of the first decade. Hand atrophy may occur later. It is common for affected individuals to become wheelchair dependent, often by age 30 years [Claramunt et al 2005].
Mild sensory loss, absent tendon reflexes, skeletal deformities, and scoliosis can be observed. Vocal cord paresis may occur [Sevilla et al 2003, Stojkovic et al 2004].
Some families with CMT4A have features of a demyelinating neuropathy, whereas others have features of axonal neuropathy [Nelis et al 2002b, Claramunt et al 2005, Kabzinska et al 2006b]. NCVs range from very slow to normal (from 18 to >50 m/s) [Ammar et al 2003, Senderek et al 2003a].
Nerve biopsy reveals hypomyelination with onion bulbs composed of basal laminae [Bornemann et al 1996, Nelis et al 2002b, Kabzinska et al 2005, Kabzinska et al 2006b].
Cerebrospinal fluid protein concentration is normal.
CMT4B1 was first described in an Italian family by Quattrone et al [1996]. Five families of Italian and Saudi Arabian ancestry have been reported [Bolino et al 2000, Houlden 2001]. Nelis et al [2002a] and Parman et al [2004] reported two additional families showing variability in age of onset and severity. Progressive distal and proximal weakness of the lower limbs is noted in early childhood (mean onset age 34 months). Pes cavus foot deformity is common and a few individuals develop facial weakness.
Adults who are affected are seriously handicapped and frequently require wheelchairs by age 20 years. Duration of illness ranges from age 27 to 39 years and death occurs in the fourth or fifth decade. Intellect is normal.
Auditory evoked potentials are abnormal.
NCVs are very slow (15-17 m/s) and often undetectable.
Sural nerve biopsy reveals irregular redundant loops of focally folded myelin.
CMT4B2 was identified in a Turkish family with a severe sensorimotor neuropathy with slow nerve conduction and focally folded myelin [Othmane et al 1999]. Azzedine et al [2003] identified two families from Tunisia and Morocco who also had early-onset glaucoma. Additional families have been reported [Conforti et al 2004] including one with juvenile glaucoma [Hirano et al 2004].
A Japanese family with neuropathy and nerve pathology showing irregular redundant loops and folding of the myelin sheath has been associated with juvenile onset of glaucoma [Kiwaki et al 2000]. A mutation in SBF2 was identified in this family [Hirano et al 2004].
CMT4C was initially reported in consanguineous Algerian families [LeGuern et al 1996], and subsequently in families from other countries of North Africa and western Europe [Gabreels-Festen et al 1999, Senderek et al 2003b, Parman et al 2004]. Onset is in childhood or adolescence, often associated with pes cavus foot deformity and a mild walking disability with a progressive, often severe, scoliosis after a 15-year disease duration.
Affected individuals have motor and sensory neuropathy in the lower limbs and slow median NCV (mean is 24 m/s).
Nerve biopsy shows an increase of basal membranes around demyelinated and unmyelinated axons, relatively few classic onion bulbs, and large cytoplasmic extensions of the Schwann cells [Gabreels-Festen et al 1999].
CMT4D has been reported in Bulgarian Gypsies originating from the community of Lom on the Danube [Kalaydjieva et al 1996, Kalaydjieva et al 1998]. Progressive sensory motor neuropathy with slow NCVs is present and foot deformity is common [Guergueltcheva et al 2006].
CMT4D has the distinguishing clinical characteristic of sensorineural deafness, with onset usually in the third decade.
A non-Gyspy family with CNS white matter lesions has been reported [Echaniz-Laguna et al 2007].
Nerve biopsy shows a hypertrophic onion bulb change.
CMT4E is a congenital hypomyelinating neuropathy (CHN) with early-onset slow NCVs and a Dejerine Sottas syndrome-like presentation (see Nomenclature) [Boerkoel et al 2001a, Chung et al 2005].
CMT4F is the designation for a severe demyelinating neuropathy with slow NCVs reported in three families [Delague et al 2000, Guilbot et al 2001, Boerkoel et al 2001b, Kijima et al 2004, Parman et al 2004].
Takashima et al [2002] described sibs homozygous for the PRX mutation p.Cys715X in whom the phenotype was initially a marked sensory neuropathy with prominent demyelinating features.
A child with a different homozygous mutation (p.Arg82fsx96) had delayed motor milestones and marked weakness. Additional families are described by Kabzinska et al [2006a] and Otagiri et al [2006].
Sural nerve pathology showed demyelination, onion bulbs, and focal myelin thickening.
CMT4H was reported by De Sandre-Giovannoli et al [2005] as a severe demyelinating neuropathy linked to 12p11.2- p13.1. Associated findings are severe scoliosis, loss of myelinated nerve fibers, and outfoldings of the myelin sheath [Stendel et al 2007].
CMT4J is a syndrome of severe childhood-onset demyelinating neuropathy [Chow et al 2007].
No specific consistent correlations are known.
CMT4B1. In a family with a MTMR2 mutation and a 17p11.2 duplication, the phenotype was severe early childhood-onset demyelinating neuropathy [Verny et al 2004].
Severe neuropathy with slow NCVs and onset in early childhood is often called the Dejerine-Sottas syndrome (DSS). This is a descriptive clinical term that does not refer to a specific disease because it is caused by mutations in multiple genes [Plante-Bordeneuve & Said 2002] (see CMT Overview).
The overall prevalence of hereditary neuropathies is estimated to be approximately 30:100,000 population. More than half of these cases are CMT type 1 (15:100,000).
The autosomal recessive forms of CMT are quite rare and often limited to specific ethnic groups (such as North Africa) where they may be relatively common.
Founder effects are observed for the GDAP1 mutations p.Gln163X in Spain [Claramunt et al 2005] and p.Met116Arg in Italy [Di Maria et al 2004].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
See CMT Overview for a discussion of approach to diagnosis of other autosomal recessive disorders with peripheral neuropathy.
CMT1E. Autosomal recessive inheritance of severe neuropathy has also occasionally been reported with homozygosity for point mutations in the PMP22 gene, in which heterozygous mutations typically cause the CMT1 phenotype. Parman et al [1999] and Numakura et al [2000] reported mutations in codon 157 of the PMP22 gene. The family reported by Parman et al [1999] included three sibs homozygous for the mutation and heterozygous, consanguineous, unaffected parents.
CMT2B1 is inherited in an autosomal recessive manner.
Other unclassified autosomal recessive neuropathies. An autosomal recessive severe sensorimotor neuropathy with mental retardation and agenesis of the corpus callosum has been reported from Quebec. It is caused by mutations in the gene encoding the K-C1 cotransporter [Howard et al 2002].
A hereditary axonal neuropathy described in a large consanguineous Moroccan family begins in the second decade and is associated with areflexia, distal and/or proximal muscle weakness and atrophy, and pes cavus. The disease has been linked to chromosome1q21 [Bouhouche et al 1999].
Thomas et al [1999] described a motor and sensory neuropathy with acrodystrophy causing severe distal sensory loss leading to prominent mutilating changes.
In Algerian families, an autosomal recessive childhood- or adult-onset axonal neuropathy with progressively severe muscle weakness and wasting has been attributed to a unique homozygous mutation (p.Arg298Cys) in the LMNA gene that encodes the lamin A/C nuclear envelope proteins [De Sandre-Giovannoli et al 2002, Tazir et al 2004]. The same gene is mutated in several other genetic diseases, including CMT2B1 and Hutchinson-Gilford progeria syndrome.
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4 (CMT4), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
NCV to help determine whether the disease is axonal, demyelinating, or mixed
Detailed family history
The 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:
Special shoes, including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking [Carter et al 1995]
Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000]
Forearm crutches or canes for gait stability; fewer than 5% of affected individuals need wheelchairs.
Exercise within the individual's capability to remain physically active
No treatment for CMT that reverses or slows the natural disease process exists.
Daily heel cord stretching exercises are helpful in preventing Achilles' tendon shortening.
Children's feet should be watched at regular intervals to provide for properly fitting shoes and avoid sores and skin breakdown.
Obesity makes walking more difficult.
Drugs and medications such as vincristine, isoniazid, taxol, cisplatin, and nitrofurantoin cause nerve damage [Graf et al 1996, Chaudhry et al 2003].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Career and employment may be influenced by the persistent weakness of hands and/or feet.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this GeneReview (CMT4A, 4B1, 4B2, 4C, 4D, 4E, 4F, 4H, 4J) are inherited in an autosomal recessive manner.
Parents of a proband
Parents of an affected individual are obligate heterozygotes and therefore carriers of the CMT4 subtype-related gene mutation present in the proband.
Heterozygotes 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 unaffected and a carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier for the CMT4 subtype-related gene mutation present in the proband is 2/3.
Offspring of a proband. The offspring of an individual with CMT4 are obligate heterozygotes (carriers) of the CMT4 subtype-related mutation present in the proband.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing is available on a clinical basis once the disease-causing mutations have been identified in an affected family member.
Family planning
The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
DNA banking. 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. DNA banking is particularly relevant when molecular genetic testing is available on a research basis only or when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk for some types of CMT4 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation if both disease-causing alleles have been identified in the family.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
If no laboratory offering prenatal testing for a subtype of CMT4 is listed in the GeneTests Laboratory Directory, prenatal testing may be available for families in which a disease-causing mutation has been identified through a laboratory offering custom prenatal testing, see .
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|---|
CMT4A | GDAP1 | 8q13-q21.1 | Ganglioside-induced differentiation-associated protein 1 |
CMT4B1 | MTMR2 | 11q22 | Myotubularin-related protein 2 |
CMT4B2 | SBF2 | 11p15 | Myotubularin-related protein 13 |
CMT4C | SH3TC2 | 5q32 | SH3 domain and tetratricopeptide repeats-containing protein 2 |
CMT4D | NDRG1 | 8q24.3 | Protein NDRG1 |
CMT4E | EGR2 | 10q21.1-q22.1 | Early growth response protein 2 |
CMT4F | PRX | 19q13.1-q13.2 | Periaxin |
CMT4H | FGD4 | 12p11.2-q13.1 | FYVE, RhoGEF and PH domain-containing protein 4 |
CMT4J | FIG4 | 6q21 | Phosphatidylinositol 3, 5 biphosphate |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
129010 | EARLY GROWTH RESPONSE 2; EGR2 |
145900 | HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS |
214400 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4A; CMT4A |
601382 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B1; CMT4B1 |
601455 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4D; CMT4D |
601596 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4C; CMT4C |
603557 | MYOTUBULARIN-RELATED PROTEIN 2; MTMR2 |
604563 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B2; CMT4B2 |
605253 | NEUROPATHY, CONGENITAL HYPOMYELINATING |
605262 | NMYC DOWNSTREAM-REGULATED GENE 1; NDRG1 |
605725 | PERIAXIN; PRX |
606598 | GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1 |
607697 | SET-BINDING FACTOR 2; SBF2 |
608206 | SH3 DOMAIN AND TETRATRICOPEPTIDE REPEAT DOMAIN 2; SH3TC2 |
609311 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4H; CMT4H |
609390 | KIAA0274 |
611104 | FYVE, RhoGEF, AND PH DOMAIN-CONTAINING PROTEIN 4; FGD4 |
611228 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4J; CMT4J |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
GDAP1
Normal allelic variants. Six exons, 13.9 kb, ORF of 1,007 nt
Pathologic allelic variants. Nonsense, missense, and frameshift mutations
Normal gene product. Ganglioside-induced differentiation-associated protein 1 [Baxter et al 2002]. The protein is highly expressed in neuronal mitochondria [Pedrola et al 2005].
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.
MTMR2
Normal allelic variants. 15 exons with an ORF of 1,932 bp
Pathologic allelic variants. Missense mutations
Normal gene product. Myotubularin-related protein 2 (MTMR2), a 643-amino acid protein, dephosphorylates phosphatidylinositol 3-phosphate. MTMR2 may interact with SBF2/MTMR13, the protein involved in CMT4B2.
Abnormal gene product. Reduced phosphatase activity could cause malfunction of neural membrane recycling or trafficking [Berger et al 2002]. A mouse model with the p.Glu276X mutation has been produced [Bonneick et al 2005].
SBF2 (CMT4B2/MTMR13)
Normal allelic variants. SET-binding factor 2 (also called myotubularin-related 13 gene) has at least 40 exons spanning about 600 kb.
Pathologic allelic variants. One family with CMT4B2 has a homozygous in-frame deletion of SBF2 exons 11 and 12 [Senderek et al 2003c]. Two nonsense mutations in exons 23 and 27 have been reported [Azzedine et al 2003].
Normal gene product. SBF2 is an 1849-amino acid member of the pseudophosphatase branch of myotubularins with striking homology to MTMR2, which is mutated in CMT4B1. MTM1 is mutated in X-linked myotubular myopathy.
Abnormal gene product. The mutation associated with SBF2 is predicted to disrupt an N-terminal domain of SBF2 that is highly conserved and may be important in sequestering proteins in the cytoplastic compartment.
SH3TC2
Normal allelic variants. 62 kb of genomic sequence with 18 exons; alternatively spliced at exon 6, between exons 8 and 9 and retention of intron 10
Pathologic allelic variants. Eight protein-truncating mutations and three missense mutations (homozygous or compound heterozygous) [Senderek et al 2003b]
Normal gene product. The ORF predicts a protein of 1,288 amino acids with no known function.
Abnormal gene product. Mutations may disrupt the formation of protein complexes.
NDRG1
Normal allelic variants. 60 kb of genomic DNA containing 16 exons, including an untranslated first exon
Pathologic allelic variants. A premature termination codon at position 148 (p.Arg148X) [Kalaydjieva et al 2000]
Normal gene product. Protein NDRG1 is proposed to be involved in growth arrest and cell differentiation during development. It is highly expressed in peripheral nerves and Schwann cells.
Abnormal gene product. May have abnormal interaction with PMP22 preventing development and maintenance of peripheral nerve/Schwann cell function and integrity.
EGR2
Normal allelic variants. EGR2 spans 4.3 kb and has two coding exons.
Pathologic allelic variants. Homozygosity for p.Ile268Asn causes a recessive neuropathy [Warner et al 1998].
Normal gene product. Early growth response protein 2. Zinc finger transcription factor. Ortholog of maurine Krox-2. Induces expression of several proteins involved in myelin sheath formation and maintenance.
Abnormal gene product. Krox-2 null mice show a block of Schwann cell differentiation.
PRX
Normal allelic variants. Boerkoel et al [2001b] found two PRX transcripts of 4853 and 5502 bp, excluding the polyA tails. The shorter mRNA is transcribed from seven exons and the deduced coding sequence extends from exon 4 through exon 7. The longer transcript arises by retention of intron 6, which introduces a stop codon and results in a truncated protein with an intron-encoded carboxyl terminus of 21 amino acids.
Pathologic allelic variants. Nonsense and frameshift mutations. The mutation p.Arg1070X is a mutation hot spot [Otagiri et al 2006].
Normal gene product. L and S periaxin, cytoskeletal proteins that may regulate Schwann cell shape and bind dystroglycan dystrophin-related protein-2. Found in the paranodal region of mature myelin sheaths. As myelin matures, periaxin moves from the adaxonal to the abaxonal membrane [Saifi et al 2003].
Abnormal gene product. Mice disrupted for PRX develop PNS compact myelin that degenerates as animals age [Gillespie et al 2000].
FGD4
Normal allelic variants. FGD4 has 17 exons whose transcript is 2931 bp long [Delague et al 2007].
Pathologic allelic variants. Homozygous missense variants (c.893T>G and c.893T>C) [Delague et al 2007] as well as nonsense and frameshift mutations are reported [Stendel et al 2007].
Normal gene product. FGD4 encodes FYVE, RhoGEF and PH domain-containing protein 4 (frabin), a 766 aa protein nucleotide exchange factor mediating actin cytoskeletal changes.
Abnormal gene product. Rat spiral motoneurons with FGD4 mutations have reduced microspike formation [Delague et al 2007].
FIG4
Normal allelic variants. FIG4 has 23 coding exons.
Pathologic allelic variants. In four families, the p.Ile41Thr missense mutation in exon 2 occurs with several other protein truncating mutations in affected compound heterozygous persons [Chow et al 2007].
Normal gene product. Phosphatidylinositol 3, 5 biphosphate (PtdIns (3,5) P2)
Abnormal gene product. Mice with a mutation in the Fig4 gene (pale tremor mouse) have a complex phenotype that includes peripheral neuropathy and neurodegeneration in autonomic ganglia, cerebral cortex and deep cerebellar nuclei, skin, and spleen [Chow et al 2007].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
Charcot-Marie-Tooth Association
2700 Chestnut Street
Chester PA 19013-4867
Phone: 800-606-CMTA (800-606-2682); 610-499-9264; 610-499-9265
Fax: 610-499-9267
Email: info@charcot-marie-tooth.org
www.charcot-marie-tooth.org
European Charcot-Marie-Tooth Consortium
Department of Molecular Genetics
University of Antwerp
Antwerp B-2610
Belgium
Fax: 03 2651002
Email: gisele.smeyers@ua.ac.be
The Hereditary Neuropathy Foundation
1751 2nd Ave Suite 103
New York NY 10128
Phone: 877-463-1287; 212-722-8396
Email: email: info@hnf-cure.org
www.hnf-cure.org
National Library of Medicine Genetics Home Reference
Charcot-Marie-Tooth disease
NCBI Genes and Disease
Charcot-Marie-Tooth syndrome
European Neuromuscular Centre (ENMC)
Lt. Gen. van Heutszlaan 6
3743 JN Baarn
Netherlands
Phone: 035 54 80 481
Fax: 035 54 80 499
Email: info@enmc.org
www.enmc.org
Muscular Dystrophy Association (MDA)
3300 East Sunrise Drive
Tucson AZ 85718-3208
Phone: 800-FIGHT-MD (800-344-4863); 520-529-2000
Fax: 520-529-5300
Email: mda@mdausa.org
www.mdausa.org
Muscular Dystrophy Campaign
7-11 Prescott Place
SW4 6BS
United Kingdom
Phone: (+44) 0 020 7720 8055
Fax: (+44) 0 020 7498 0670
Email: info@muscular-dystrophy.org
www.muscular-dystrophy.org
Teaching Case-Genetic Tools
Cases designed for teaching genetics in the primary care setting.
Case 7. Resident Receives a Troubling Phone Call about Peripheral Neuropathy from a Patient's Relative
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
30 April 2009 (cd) Revision: sequence analysis available clinically for CMT4H
12 June 2008 (cd) Revision: sequence analysis of entire NDRG1 coding region available clinically
6 September 2007 (me) Comprehensive update posted to live Web site
15 April 2005 (me) Comprehensive update posted to live Web site
19 December 2003 (tb) Author revisions
24 October 2003 (cd,tb) Revision: change in test availability
21 August 2003 (cd,tb) Revision: change in gene name
29 May 2003 (tb) Author revisions
4 April 2003 (me) Comprehensive update posted to live Web site
8 November 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
22 June 2001 (tb) Author revisions
11 April 2001 (tb) Author revisions
25 September 2000 (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
14 January 2000 (tb) Author revisions
24 September 1999 (tb) Author revisions
31 August 1999 (tb) Author revisions
18 June 1999 (tb) Author revisions
8 April 1999 (tb) Author revisions
24 September 1998 (tb) Review posted to live Web site
April 1996 (tb) Original submission