|
|
Dejerine-Sottas Disease (DS)
Charcot-Marie-Tooth Disease.A hereditary neurological disorder characterized by demyelination of motor nerves resulting in progressive distal muscle weakness. incidence: rare age of onset: infancy risk factors: familial - autosomal recessive M = F a group of hereditary disorders characterized by progressive distal muscle weakness also called Peroneal Muscular Atrophy 
motor nerves are predominantly affected with sensory and autonomic nerve involvement occurring later there are 3 clinical variants: 
Type I - Charcot-Marie-Tooth Disease Type II Type III - Dejerine-Sottas Disease can be subdivided into demyelinating (Types I and III) and non-demyelinating or neuronal (Type II) 
Dejerine-Sottas Disease is differentiated from Charcot-Marie-Tooth Disease by an autosomal recessive inheritence and an earlier onset of muscle weakness with subsequent more severe course genetic defect -> demyelination of peripheral motor nerves -> peroneal and tibial nerves most severely affected -> progres-sive atrophy of the muscles of the anterior compartment of the lower legs -> progressive weakness of the distal muscles of the lower limb with gait disturbances distal muscle weakness gross motor developmental delay with infantile hypotonia; patients may never run properly - pes cavus deformity due to denervation of the intrinsic foot muscles loss of distal deep tendon reflexes -> areflexia 
distal muscle weakness atrophy of muscles of the forearm and hands may occur but is usually a late finding contractures of the wrists and fingers may produce a "claw hand" progressive loss of proprioception and vibration sense with involvement of large myelinated nerve fibres - may also loose sensation to pain and temperature - tingling or burning sensations of the feet (rarely pain) lack of reaction to light Argyll-Robertson pupil kyphoscoliosis extremely low NCV extensive segmental demyelination and remyelination hypomyelination characteristic "onion-bulb formations" of proliferated Schwann cell cytoplasm surrounding axons -> affected nerves become palpably enlarged more pronouned than in Charcot-Marie-Tooth Disease cycles of denervation/reinnervation elevated CSF protein and CPK no treatment for underlying disease multidisciplinary approach Paediatrics, Neurology, Orthopedics, Physiotherapy genetic counselling strengthening exercises to the feet and legs active stretching of the feet polypropylene ankle-foot orthoses to stabilize feet and re-duce falling special adaptive devices for hands if affected - utensils, writing most patients are confined to a wheelchair by the 2nd or 3rd decade of life hereditary disorder slowly progressive muscle weakness in the feet, lower legs, hands and forearms, and a mild loss of sensation in limbs, fingers, and toes. The weakness results from the degeneration of nerves that stimulate muscle rather than from a degenerative process in the muscle tissue itself. The disorder, named for three physicians who first identified it in 1886, is also known as peroneal muscular atrophy because if primarily affects the peroneal muscles, which are located in the lower leg. There are now thought to be at least two types of the disease - hypertrophic and neuronal - that differ to some degree in severity. In both types of Charcot-Marie-Tooth disease, there is normal life expectancy, limited disability, and very slow progression of the disease. Some patients, however, experience rapid progression and severe disability. usually foot deformities (high arch and flexed toes) and difficulty in walking caused by these structural changes. Typically, the knees have to be raised higher than normal to lift feet off the ground. there is also a tendency to sprain ankles and some difficulty in maintaining balance while standing. How does the disease progress? As the disorder advances, muscles in the lower legs and sometimes lower third of the thighs become weak and reduced in size (atrophic). Hands and forearms are affected in later stages, and fine manipulatory acts may become difficult. In addition, the sense of touch is somewhat diminished in the limbs and extremities. Because of the slow progression of the disease, its onset is often difficult to determine. Generally some foot deformity occurs before age twenty in the hypertrophic type. In the neuronal type, symptoms usually develop later, in early adult life or middle age. In what other ways do the hypertrophic and neuronal types differ? The small muscles of the hand are more affected in the hypertrophic type than they are in the neuronal, and sensory changes are more pronounced. This form of Charcot-Marie-Tooth disease is also characterised by enlarged (hypertrophic) nerves and by degeneration of the sheath of fatty material (myelin) that insulates many of the body's nerve fibres. The neuronal form of Charcot-Marie-Tooth disease affects lower limb functions more than the hypertrophic form, and there is comparatively greater loss of muscle bulk below the knee. Weakness in the ankles and feet is also likely to be more severe in the neuronal type. The disease is usually inherited as a dominant trait in both the hypertrophic and neuronal types. This means that it is only necessary for one parent to carry the defective gene for the disease to be transmitted. It also means that this parent will have the disease, although he or she might be unaware of it if the disorder is very mild with no apparent symptoms. There is a fifty percent chance that a child will inherit the disorder if either parent carries the gene. Male and female children are equally affected. Diagnosis is usually made through a physical examination that includes tests of muscle function and sensory responses, supplemented with a laboratory test (electromyogram) that measures the electrical activity of muscle cells. In addition, a complete family medical history is taken to determine if the patient's disorder is an inherited one. In some cases, nerve and muscle biopsies confirm the diagnosis, especially when symptoms are very mild and family history of the disease is not apparent. Both electromyography and muscle biopsy tests help to distinguish between the hypertrophic and neuronal types of the disorder.There is no known cure for Charcot-Marie-Tooth disease. However, foot deformities can be treated with carefully fitted shoes and proper foot care. A regular program of moderate excerise can build up muscles and increase the mobility of joints. HMSN is the commonest cause of the peroneal muscular atrophy syndrome consisting of distal leg muscle wasting and weakness, usually with a pes cavus foot deformity. HMSN Old polio infection Friederich's ataxia Spina bifida The characteristic clinical features include distal wasting of the lower limb muscles (the so-called 'inverted champagne bottle' appearance). The feet show pes cavus and clawing of the toes, with weakness of the feet extensors. The ankle jerks are absent and the plantar reflexes show no response (occasionally they can be extensor). Palpable nerve thickening is found in about 25% of cases and is specific for the demyelinating forms of HMSN. The patient may have a 'high stepping gait' due to bilateral foot drop. There may be wasting of the small muscles of the hand. In general, the presenting symptoms are due to difficulty walking or a foot deformity. The inheritance is usually autosomal dominant, but recessive forms also occurCMT type 1 is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity (NCV). It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Patients usually become symptomatic between five and 25 years of age. Fewer than 5% of patients became wheelchair dependent. Lifespan is not shortened.CMT1A represents 70 to 80% of all CMT1 involves abnormalities of the PMP-22 gene on chromosome 17p11. The most common mutation causing CMT1A is a duplication of 17p11 involving the PMP-22 gene. The testing for this duplication detects about 98% of patients with CMT1A and is available in clinical laboratories. Testing is also available for point mutations in the PMP-22 gene, which account for the other approximately 2% of patients with CMT1A. CMT1B, which is much less common than CMT1A, is associated with point mutations in the MPZ gene (myelin P0 protein) for which molecular molecular genetic testing is available clinically. Very rarely mutations occur in the EGR2 (early growth response 2) gene causing CMT1D, for which molecular genetic is also available clinically. CMT1 is inherited in an autosomal dominant manner. Most probands with CMT1 have inherited the disease-causing mutation, but some have it as the result of a de novo gene mutation. The offspring of an affected individual has a 50% risk of inheriting the altered gene. Prenatal testing is possible when a disease-causing mutation has been identified in an affected family member. Requests for prenatal testing for typically adult-onset diseases that do not affect intellect or lifespan are uncommon.The diagnosis of CMT type 1 is suspected in individuals with a progressive peripheral motor and sensory neuropathy with slow nerve conduction velocities (NCV) and a family history consistent with autosomal dominant inheritance. Clinically available molecular genetic testing identifies mutations in the PMP-22, MPZ, or EGR2 genes in the majority of patients with the CMT type 1 syndrome. A motor and sensory neuropathy Slow nerve conduction (NCV) typically 10-30 meters/second (normal being greater than 40-45 m/s) Palpably enlarged nerves, especially the ulnar nerve and greater posterior auricular nerve A family history consistent with autosomal dominant inheritance 
Seventy to eighty percent of CMT1 is designated CMT1A and is caused by an alteration of the PMP-22 gene (chromosomal locus 17p11). About 5-10% of CMT1 is designated CMT1B and is caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosomal locus 1q22). The remaining ~15% of CMT1 is designated CMT1C or CMT1D. No gene has been identified for CMT1C but mutations in the EGR2 gene (chromosomal locus 10q21) are associated with CMT1D. CMT1A is most commonly caused by duplication of the PMP-22 gene on one chromosome 17p11, resulting in the presence of three copies of the PMP-22 gene. The most reliable test for CMT1A utilizes pulsed field gel electrophoresis, is widely available and detects >98% of patients with CMT1A. A specialized fluorescent in situ hybridization (FISH) assay is available from a limited number of clinical laboratories [Shaffer et al 1997]. Point mutations in the PMP-22 gene cause <2% of cases of CMT1A and are not identified by the techniques used to identify duplications. Testing for point mutations in the PMP-22 gene is also clinically available. CMT1B is caused by alterations of the MPZ gene (myelin P0 protein). Testing for CMT1B is available in clinical laboratories. A few rare families with the CMT1 syndrome have been found to have point mutations in the EGR2 gene [Warner 1998; Nelis, Timmerman et al 1999]. Testing is clinically available. Table 1: Molecular Genetic Testing Used in the Diagnosis of CMT1 Subtype of CMT1(% of CMT1)
|
% of Patients with Positive Test Results
|
Genetic Mechanism
|
Test Type
|
Test Availability
|
CMT1A
(70-80%)
|
>98%
|
Duplication of PMP-22
|
DNA or FISH-based
|
Clinical
|
<2%
|
Point mutation in PMP-22
|
DNA
|
Research
|
|
CMT1B
(5-10%)
|
100%
|
Point mutation in MPZ
|
DNA
|
Clinical
|
CMT1C
(10-15%)
|
Unknown
|
Unknown
|
None
|
Research
|
CMT1D
EGR2 type (<5%)
|
<2%
|
Point mutations in EGR2
|
DNA
|
Clinical
|
The other phenotypes associated with mutations of PMP-22 are hereditary liability to pressure palsies (HNPP), caused by deletions of PMP-22, and very rare autosomal recessive neuropathy (CMT4) caused by point mutations in PMP-22 [Parman et al 1999]. The other phenotype which has been associated with mutations in the MPZ gene is the CMT2 phenotype.The typical presenting symptom of CMT1 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. The typical adult patient has bilateral foot drop, symmetrical atrophy of muscles below the knee (stork leg appearance), atrophy of intrinsic hand muscles, and absent tendon reflexes in both upper and lower extremities [Dyck et al 1993]. Proximal muscles usually remain strong. Mild to moderate sensory loss including deficits of position, vibration, and pain/temperature commonly occurs in the feet. Pain, especially in the feet, is reported by 20%-30% of patients [Carter et al 1998]. The pain is often musculoskeletal in origin, but may be neuropathic in some cases.In the most common forms of CMT, patients usually become symptomatic between ages five and 25 years [Carter et al 1995]. Clinical severity, from considerable weakness and disability to extremely mild disease that is unrecognized by patient and physician, is variable. Age of onset ranges from infancy with delayed walking to the fourth and subsequent decades. In CMT1A, prolonged distal motor latencies may already be present in the first months of life, and slow motor nerve conduction velocities have been found in some individuals by age two years. However, the full clinical picture may not occur until the second decade of life or later [Garcia et al 1998]. CMT is slowly progressive over many years, but patients experience long plateau periods without obvious deterioration. Many patients require ankle-foot orthoses (AFO) as adolescents or adults. Less commonly, patients need more assistance with walking and, in rare instances (<5%), need a wheelchair. The disease does not decrease lifespan. A few men with CMT have reported impotence [Bird et al 1994].The CMT1 subtypes are clinically indistinguishable and are identified solely by molecular findings. CMT1B tends to be more disabling than CMT1A with even slower NCVs (5-20 m/s) and proximal as well as distal weakness. However, some cases of CMT1B are clinically identical to CMT1A. A few patients have been described with mutations in the myelin P0 gene (CMT1B) with normal or near-normal nerve conduction velocities [Marrosu et al 1998, De Jonghe et al 1999]. CMT1C appears clinically identical to CMT1A [Chance et al 1992].In addition to these three types of CMT1, further heterogeneity in the CMT1 phenotype seems to exist. This heterogeneity includes families with inherited neuropathies associated with findings such as pyramidal tract features [Frith et al 1994] or deafness [Horoupian 1989, Kovach et al 1999], optic atrophy, and other distinctive signs [Dyck et al 1993]. A few patients have vocal cord or phrenic nerve involvement resulting in difficulty with voice or breathing. Although the autonomic nervous system may be involved, it is rarely symptomatic. Hearing loss is occasionally reported and its exact relationship to the most common form of CMT is unclear [Kovach et al 1999].are quite slow, typically 10 to 30 meters per second with a range of 10-40 m/s (normal being greater than 40-45 m/s). Nerve conduction velocities progressively slow over the first two to six years of life and are relatively stable throughout adulthood. Early onset of symptoms and severity of disease show some correlation with slower NCVs, but this is only a general trend.may be present, especially the ulnar nerve at the olecranon groove and the greater auricular nerve running along the lateral aspect of the neck.Microscopically, the enlarged nerves show hypertrophy and onion bulb formation thought to result from repeated demyelination and remyelination of Schwann cell wrappings around individual axons.The phenotype associated with some PMP-22 point mutations has onset in early childhood and is more severe than that of the 17p11 duplication; this phenotype has been called Dejerine-Sottas syndrome (DSS) [Roa et al 1993, Ionasescu et al 1995]. DSS is a confusing term because it no longer refers to a specific disease. Point mutations in both PMP-22 and MPZ have been found in patients with DSS. Most of these patients are heterozygous for de novo autosomal dominant mutations. Thirteen heterozygous missense mutations in PMP-22 are associated with DSS. Three missense mutations at codon 72 are associated with DSS, suggesting that codon 72 mutations lead to a severe phenotype [Nelis, Haites et al 1999]. In one family, sibs with DSS are homozygous for a PMP-22 point mutation (Arg157Trp), while their heterozygous parents are clinically normal [Parman et al 1999]. Autosomal recessive inheritance of a PMP-22 mutation has also been reported by Numakura et al 2000.Patients homozygous for the CMT1A duplication (who have four copies of the PMP-22 gene) have early childhood-onset of a neuropathy that is more severe than in those heterozygous for the duplication.The thr124met mutation in MPZ has been associated with late-onset sensorineural hearing loss, pupillary abnormalities, and motor nerve conduction velocities ranging from slow (24-35 m/s) to normal (48-59 m/s) [Chapon et al 1999].A point mutation in the PMP-22 gene in exon three (Ala67Pro) has been found in a family with CMT1 with deafness previously reported by Kousseff et al (1982) [Kovach et al 1999].A unique mutation in the EGR2 gene (Arg381His) has been associated with a CMT1 syndrome with sensorineural hearing loss, third cranial nerve palsy, and vocal cord palsy [Pareyson et al 2000].The overall prevalence of hereditary neuropathies is estimated to be approximately 30 per 100,000 population. The prevalence of CMT type 1 is 15 per 100,000. The prevalence of CMT1A is ~10 per 100,000.Acquired causes of neuropathy need to be excluded (see CMT Overview).The differential diagnosis includes other genetic neuropathies, especially CMTX, CMT2, CMT4, and HNPP.Many forms of genetic neuropathy exist. For a review see Charcot-Marie-Tooth Hereditary Neuropathy Overview.No treatment for CMT that reverses or slows the natural disease process exists. Treatment is symptomatic and patients are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 1995]. Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable. Special shoes, including those with good ankle support, may be needed. Patients often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking [Dyck et al 1989, Carter et al 1995]. Orthopedic surgery may be required to correct severe pes cavus deformity [Holmes 1993]. Some patients require forearm crutches or canes for gait stability, but fewer than 5% of patients need wheelchairs. Obesity is to be avoided because it makes walking more difficult. Exercise is encouraged within the patient's capability and many individuals remain physically active. Important career and employment implications exist because of the persistent weakness of hands and/or feet.Drugs and medications such as vincristine, isoniazid, and nitrofurantoin that are known to cause nerve damage should be avoided [Graf et al 1996].The cause of any pain should be identified as accurately as possible.Musculoskeletal pain may respond to acetaminophen or non-steroidal anti-inflammatory agents [Carter et al 1998]. Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.Dyck et al (1982) have described a few patients with CMT1 in whom treatment with steroids (prednisone) has produced initial but not long-term improvement. One such family had a specific MPZ gene mutation (I99T) [Donaghy et al 2000]. 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 or cultural issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see . —ED.Mode of Inheritance CMT1 is inherited an autosomal dominant manner. Molecular genetic testing is not available. For example, the disease-causing mutation in a family has not yet been elucidated or testing is available on a research or linkage basis only. Interpretation of results is difficult. For example, if an affected family member chooses not to be tested, interpretation of a "negative" result in at-risk family members is difficult. An affected family member who chooses not to be tested may be willing to have DNA banked for future use by other family members. Disease Name
|
Gene Symbol
|
Locus
|
Normal Gene Product
|
Genomic Databases
|
CMT1A
|
PMP-22
|
17p11
|
PMP-22
|
|
CMT1B
|
MPZ
|
1q22
|
Myelin P0 protein
|
|
CMT1C
|
?
|
?
|
?
|
|
CMT1D
|
EGR2
KROX20
|
10q21
|
Early growth response protein 2
|
Gene symbol: PMP-22 (peripheral myelin protein-22) Chromosomal locus: 17p11 [Vance et al 1989] Normal allelic variants: The PMP-22 gene has approximately 1,660 nucleotides and contains four exons [Patel et al 1992]. It is similar to a growth arrest specific gene in mouse and rat [Welcher et al 1991]. Disease-causing allelic variants: The molecular defect has been shown to be a 1.5 Mb duplication at 17p11, which includes the PMP-22 gene (peripheral myelin protein-22) [Lupski et al 1991, Raeymaekers et al 1991]. This duplication results from unequal crossing over of homologous chromosomes at regions of repetitive elements that flank the duplicated region. Duplication of this gene is associated with increased mRNA message for PMP-22 in peripheral nerve, and by an unknown mechanism results in abnormal myelination [Yoshikawa et al 1994, Gabriel 1997]. A relative gene dosage effect exists regarding genotype-phenotype correlation: 1) one normal gene (as in HNPP with the 17p11 deletion) [Chance et al 1993] causes a mild phenotype; 2) two normal genes represent the normal wild type condition; 3) three normal genes (as in the common CMT1A 17p11 heterozygous duplication) cause a more severe phenotype; and 4) four normal genes (as in homozygosity for the 17p11 duplication) cause the most severe phenotype. A mouse containing eight copies of the human PMP-22 gene shows a similar but more severe phenotype as CMT1A patients, while mice containing 16 and 30 additional copies of mouse PMP-22 show severe hypomyelination [Nelis, Haites et al 1999]. This supports the hypothesis that more copies of PMP-22 result in a more severe phenotype. More than 27 point mutations also occur in the PMP-22 gene and also cause a CMT1 phenotype. Individuals with point mutations tend to have more severe clinical disability than persons with a single 17p11 duplication, presumably because of a dominant negative or loss of protein function effect. Most missense mutations are localized in the trans-membrane domains of PMP-22, indicating the functional importance of these domains. Point mutations in PMP-22 causing autosomal dominant CMT1 have also been described [De Jonghe et al 1997]. Normal gene product: PMP-22 is a 160 amino acid protein that is present in compact myelin and has four transmembrane domains. Gene symbol: CMT1B, P0 myelin protein Chromosomal locus: 1q22 [Bird et al 1982, Lebo et al 1991] Normal allelic variants: The P0 gene spans approximately 7kb and contains six exons. Disease-causing allelic variants: More than 56 point mutations in the P0 myelin protein gene have been reported [Hayasaka et al 1993; Kulkens et al 1993; De Jonghe et al 1997; Nelis, Haites et al 1999]. More than 70% of the mutations are localized in exons two and three of the MPZ gene coding for the extracellular domain, indicating the functional importance of this domain. There is no specific type of mutation or specific codon associated with a specific phenotype. Normal gene product: P0 is a major structural component of peripheral myelin representing about 50% of peripheral myelin protein by weight and about 7% of Schwann cell message [Wells et al 1993]. 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. CMT type 2 is a non-demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal nerve conduction velocities. CMT2 is clinically similar to CMT1, although typically less severe. Peripheral nerves are not enlarged or hypertrophic. Several genetic subtypes have been identified by linkage analysis, but no disease-causing genes have been identified. The diagnosis is based on clinical findings and EMG/NCV characteristics. No molecular genetic tests exist.CMT2 is inherited in an autosomal dominant manner. Most probands with CMT2 have inherited the disease-causing mutation from an affected parent. The offspring of an affected individual have a 50% risk of inheriting the altered gene. Prenatal testing is not possible.The diagnosis of CMT2 is based on clinical findings and family history. Molecular genetic testing of CMT2A, 2B, 2C, 2D, and 2E is on a research basis only. A progressive peripheral motor and sensory neuropathy Normal or near-normal nerve conduction velocities (NCV) Abnormal EMG with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses [Dyck et al 1993, Nicholson 1991, Dyck et al 1994]. A family history consistent with autosomal dominant inheritance. The five subtypes of CMT2 are identical clinically and are distinguished solely on genetic linkage findings.The chromosomal loci for CMT2A, CMT2B, and CMT2D have been mapped, and only the gene for CMT2E (neurofilament-light, NF-L) has been identified in two families [Mersiyanova et al 2000, De Jonghe et al 2001]. DNA-based testing is available on a research basis only. The frequencies of the various types of CMT2 are unknown and no single type is known to predominate [Timmerman et al 1996]. CMT2C refers to two families with autosomal dominant axonal neuropathy associated with frequent vocal cord and phrenic nerve paralysis sometimes requiring tracheotomy [Dyck et al 1994]. The condition does not link to the CMT2A or CMT2B loci.Sub Type of CMT2
|
% of Patients
|
Genetic Mechanism
|
Test Availability
|
CMT2A
|
Unknown
|
Unknown
|
Research
|
CMT2B
|
|||
CMT2C
|
|||
CMT2D
|
|||
CMT2E
|
Mutation of NF-L
|
CMT2 is a disorder of peripheral nerves in which the motor system is more prominently involved than the sensory system, although both are involvedThe typical patient 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. Nerve conduction velocities (NCVs) are normal or mildly slow (30-40m/s). The clinical syndrome overlaps extensively with CMT1. In general, the patients with CMT2 (except for those with CMT2B) tend to be less disabled and have less sensory loss than those with CMT1.Patients usually become symptomatic between ages five and 25 years [Berciano 1986, Carter et al 1995, Saito 1997]. However, the range extends from earlier onset with delayed walking in infancy onset 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. The typical adult patient has bilateral foot drop, symmetrical atrophy of muscles below the knee (stork leg appearance) and absent tendon reflexes in the lower extremities. Atrophy of intrinsic hand muscles is less frequent and tendon reflexes may be intact in the upper limbs [Dyck et al 1993]. Proximal muscles usually remain strong. Mild sensory loss including 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% of patients.A few patients have vocal cord or phrenic nerve involvement resulting in difficulty with voice or breathing. CMT2 is progressive over many years, but patients experience long plateau periods without obvious deterioration. In some, the disease can be so mild as to go unrecognized by patient and physician. The disease does not decrease life span.CMT2B has prominent sensory loss with distal ulceration; controversy exists regarding its exact classification [De Jonghe et al 1997, Elliott et al 1997]. The genetic locus is 3q13-q22 and additional phenotype information is described by Auer-Grumbach et al (2000). CMT2C is associated with vocal chord and phrenic nerve paralysis [Dyck 1994]. CMT2D has prominent weakness and atrophy of the hands [Ionasescu et al 1996]. CMT2C refers to two families with autosomal dominant axonal neuropathy associated with frequent vocal cord and phrenic nerve paralysis sometimes requiring tracheotomy [Dyck et al 1994]. CMT2D is characterized by predominately distal motor weakness with wasting of the hand muscles [Ionasescu et al 1996]. This phenotype is similar to that of hereditary motor neuropathy type 5 (HMN V) and the two disorders may be allelic [Sambuughin et al 1998]. CMT2E has been reported in two families, one from Russia and one from Belgium, with a progressive sensory and motor neuropathy. The Russian family had relatively normal NCV and hyperkeratosis [Merisyanova 2000]. The Belgian family had NCVs ranging from 25 to 42 m/s [De Jonghe et al 2001]. The CMT2 phenotype with only mild slowing of NCV is sometimes caused by mutations in myelin P0 (MPZ), which typically cause CMT1B, including a single mutation that has occurred in several families (Thr124Met) [Senderak et al 2000]. The same mutation has also been associated with the CMT2 phenotype with deafness and Argyll Robertson pupils [Chapon et al 1999]. Misu et al (2000) have reported an axonal (CMT2) phenotype with marked sensory impairment and often with Adie's pupil and deafness with the T124M or D75V mutations. The CMT2 phenotype can also occur in families with CMTX (connexin-32 mutations), but such families do not show male-to-male transmission [Gutierrez et al 2000]. Molecular genetic testing is not available. For example, the disease-causing mutation in a family has not yet been elucidated or testing is available on a research or linkage basis only. Interpretation of results is difficult. For example, if an affected family member chooses not to be tested, interpretation of a "negative" result in at-risk family members is difficult. An affected family member who chooses not to be tested may be willing to have DNA banked for future use by other family members. Disease Name
|
Gene Symbol
|
Locus
|
Normal Gene
Product
|
Genomic
Databases
|
|
CMT2A
|
CMT2A
|
1p36-p35
|
|
|
|
CMT2B
|
CMT2B
|
3q13-q22
|
|
||
CMT2C
|
CMT2C
|
?
|
|
|
|
CMT2D
|
CMT2D
|
7p15
|
|
||
CMT2E
|
CMT2E
|
8p21
|
NF-L
|
|
|
DefinitionCategories Type
|
Proportion of CMT
|
CMT1
|
50%
|
CMT2
|
20-40%?
|
CMT4
|
Rare
|
CMTX
|
10-20%
|
Disease Name
|
Inheritance
|
Proportion of CMT1
|
Gene Symbol
|
Locus
|
Normal Gene Product
|
Testing
|
Genomic Databases
|
CMT1A
|
AD
|
70-80%
|
PMP-22
|
17p11
|
PMP-22
|
Clinical
|
|
CMT1B
|
AD
|
5%-10%
|
MPZ
|
1q22-q23
|
Myelin Po protein
|
Clinical
|
|
CMT1C
|
AD
|
?
|
?
|
?
|
?
|
|
|
Disease Name
|
Inheritance
|
Proportion of CMT2
|
Gene Symbol
|
Locus
|
Normal Gene Product
|
Testing
|
Genomic Databases
|
|
CMT2A
|
AD
|
Unknown
|
CMT2A
|
1p36-p35
|
?
|
Research
|
|
|
CMT2B
|
AD
|
Unknown
|
CMT2B
|
3q13-q22
|
?
|
|||
CMT2C
|
AD
|
Unknown
|
CMT2C
|
?
|
?
|
|
||
CMT2D
|
AD
|
Unknown
|
CMT2D
|
7p14
|
?
|
|||
CMT2E
|
AD
|
Unknown
|
CMT2E
|
8p21
|
NF-L
|
Research
|
|
|
Disease Name
|
Inheritance
|
Proportion of CMT4
|
Gene Symbol
|
Locus
|
Normal Gene Product
|
Testing
|
Genomic Databases
|
|
CMT4A
|
AR
|
Rare
|
CMT4A
|
8q13-q21
|
?
|
Research
|
|
|
CMT4B
|
AR
|
Rare
|
CMT4B
|
11q23
|
?
|
|||
CMT4C
|
AR
|
Rare
|
CMT4C
|
5q23-q33
|
?
|
|
||
CMT4D
|
AR
|
Rare
|
CMT4D
|
8q24
|
NDRG1
|
|||
CMT4E (?)
|
AR
|
Rare
|
(KROX20 EGR2)
|
10q21-q22
|
?
|
|||
CMT4F (?)
|
AR
|
Rare
|
PRX
|
19q13
|
Periaxin
|
|||
Disease Name
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Inheritance
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Proportion of CMTX
|
Gene Symbol
|
Locus
|
Normal Gene Product
|
Testing
|
Genomic Databases
|
|
CMTX
|
XLD
|
90%
|
GJB1
|
Xq13-q21
|
Gap junction beta-1 protein
connexin 32
|
Clinical
|
|
|
Other X-linked forms
|
|
10%
|
|
|
|
|
|
|
DiagnosisGenetic CounselingMost individuals diagnosed as having Charcot-Marie-Tooth hereditary neuropathy have an affected parent. Occasionally the family history is negative. Family history may be "negative" because of failure to recognize Charcot-Marie-Tooth hereditary neuropathy in family members, late onset in a parent, reduced penetrance of the mutant allele in an asymptomatic parent, or a new mutation for the gene causing Charcot-Marie-Tooth hereditary neuropathy. New mutations causing Charcot-Marie-Tooth hereditary neuropathy are relatively uncommon, but have been reported on several occasions. If one of the proband's parents has a mutant allele, then the risk to the sibs to inherit the mutant allele is 50%. The age of onset and degree of disability is not entirely predictable in members of the same family or in different families with the same mutation, but there is a strong tendency for the phenotypes to be highly similar. The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation. Heterozygotes are asymptomatic. At conception, the sibs have a 25% chance of being affected, a 50% chance of being unaffected, and a 25% chance of being unaffected and not a carrier. The unaffected sibs of an affected individual have a 2/3 chance of being heterozygous. Heterozygotes are asymptomatic. Women who have an affected son and another affected male relative are obligate heterozygotes. CMTX is considered an X-linked dominant because males are consistently more severely affected than females. Heterozygote females may be normal, or, more often, have mild to moderate signs and symptoms. A female who has a CMTX mutation has a 50% chance of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation may be normal but more often will have mild to moderate signs and symptoms. If the mother does not have the CMTX mutation that has been identified in her son, the risk to sibs is low but not zero since the incidence of germline mosaicism in mothers is not known. All the daughters of an affected male will inherit the CMTX mutation and may be normal but, more often, will have mild to moderate signs and symptoms. None of his sons will be affected. Molecular genetic testing is not available. For example, the gene responsible has not yet been identified, the disease causing mutations have not yet been elucidated or testing is available on a research or linkage basis only. Molecular genetic testing is not informative. For example, linkage testing was not informative or the sensitivity of currently available testing is less than 100%. Interpretation of results is difficult. For example, if an affected family member chooses not to be tested, interpretation of a “negative” result in at risk family members is difficult. An affected family member who chooses not to be tested may be willing to have DNA banked for future use by other family members.