Types of Charcot-Marie-Tooth Disease
by Dorothy B. Gosling, R.N. (1999)

I would like to thank Dr. Alan Pestronk M.D., Professor, Departments of Neurology and Pathology, Director,Neuromuscular Division & Neuromuscular Clinical Laboratory,Washington University School of Medicine,St. Louis, MO for permission to use the information on his website: http://www.neuro.wustl.edu/neuromuscular/time/hmsn.html
This article is written for information purposes only and was believed to be accurate at the time this article was written. Every individual should consult his/her personal physician if he/she has questions arising from this document.

CMT TYPE 1 (occurs approximately 15 per 100,000 population)
This type is the demyelinating or hypertrophic form which means that the covering over the nerves (myelin sheath) breaks down exposing the nerve fiber.

CMT 1A with duplication (approximately 10.5 per 100,000 population)
There is an incidence of 18% sporadic cases with no family history with 60% having a family history of CMT. Males and females are equally affected. It is usually carried by the male side of the family (89%). Maternal origin rare at 11% of cases.
Gene defect is found on Chromosome 17 in the Peripheral Myelin Protein 22 located at p11.2 - p12. With duplication in CMT there are three copies of the gene in CMT. (The more copies there are of the gene usually increases the severity of the disease). The term you have probably seen is "extra genetic material." People without CMT have two copies of the gene.
Inheritance: autosomal dominant, meaning there is a 50% chance in each pregnancy of each child of the affected person having CMT.
Onset of this type occurs in first 10 years of life in 75%, 10% between the ages of 10 and 20, but there are rare cases where the person has no symptoms in their 30s.
EMG studies show slowing of the nerve conduction (speed of impulse) through the affected nerves and there is no nerve conduction block (total interruption of nerve impulse). The slowing is apparent before symptoms appear.
Nerve biopsy shows the myelin sheath to be thicker than normal, with areas of demyelination (break down of the myelin sheath) and formation of small ‘onion bulbs' (swellings) on the nerves.
Initial clinical signs: difficulty walking, and foot deformities; strength reduced in feet and hands, but may be normal above wrists and knees; reduced or absent reflexes, with wide variations in symptoms; weakness and wasting of feet and hands; rare occurrence of respiratory involvement; mild sensation loss, with no numbness or pins and needles.
Genetic testing (DNA) is available for this type of CMT.

CMT 1A with point mutation
Gene defect is also on Chromosome 17, but is in the Myelin Protein Zero gene, where a Point Mutation occurs to cause the CMT.
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child of the affected person having CMT. It is usually more severe than duplication but in some families there are people with few to no signs.
Onset occurs before the age of six years.
EMG studies show a very slow nerve conduction speed, slower than in 1A with duplication.
Nerve biopsy shows that the myelin sheath is thinner than normal with areas of demyelination (break down of the myelin sheath) and the ‘onion bulbs' (swellings on the nerve fibers) formed are large and occur on most nerve fibers(inside the myelin sheath).
Clinical signs: difficulty walking, and foot deformities; strength reduced in feet and hands, but may be normal above wrists and knees; reduced or absent reflexes, with wide variations in symptoms; weakness and wasting of feet and hands; rare occurrence of respiratory involvement; mild sensation loss. Symptoms are usually more severe than 1A with duplication and can have limited central nervous system involvement.
Genetic testing is also available for this type.

CMT TYPE 1A homozygous
Gene defect is on Chromosome 17 but there are four copies of the Peripheral Myelin Protein 22 gene. (Homozygous means that the genes received by the affected person from the parents are similar genes...e.g. interfamilial marriages, etc).
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset is usually under one year of age.
EMG studies show extremely slow nerve conduction speed.
Nerve biopsy shows severe demyelination of the myelin sheath.
Clinical signs show the most severe weakness usually from birth
Genetic testing is available.

CMT1A recessive
Gene defect is on Chromosome 17, in the Peripheral Myelin Protein 22 gene. However, the defect is a point mutation in this gene with a deletion of some genetic material (missing genetic material).
Inheritance: autosomal recessive which means that both parents must have the defect to have a child with CMT and there is a 25% chance of having an affected child for each pregnancy.
Onset is usually at birth.
Clincial symptoms: very severe type with severe weakness.
Genetic testing is available.

CMT Type 1: EGR2 mutation Autosomal Dominant
Gene defect: Chromosome 10q21. 1-q22.1
Inheritance: both autosomal dominant and autosomal recessive.
Onset: 10 to 20 years of age.
EMG: nerve conduction speed moderately slow.
Clinical signs: weakness of feet and hands.
Genetic testing is available.


CMT TYPE 1B
Gene defect is found on Chromosome 1q22 in the Myelin Protein Zero gene. Point mutations occur in many different locations in the gene. Each mutation that has been found correlates with different severity of the CMT.
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset usually occurs before the age of 10 years, occasionally 10 to 20 years, rare over 30 years.
EMG studies show very slow nerve conduction speed of less than 20 metres/second, rarely have near normal NCVs.
Nerve biopsy: two types of 1B have been defined with genetic testing. Biopsy shows that in one type the nerves are not enlarged, 23% to 68% of fibers with a myelin sheath are demyelinated, but there are few axons (nerve fibers) that are involved. In the other type the myelin sheath becomes folded on itself producing nerve fiber death.
Clinical signs: total loss of reflexes in the lower leg, feet, forearms and hands; sensation loss is mild; delayed walking as a baby, with difficulty due to weakness and foot deformities; no central nervous system involvement; severe disability in some by 20 years to 40 years of age.
Genetic testing is available at selected labs.

CMT Type 1 X-linked
X-linked CMT is only inherited through the mother as the defect is on the ‘X' chromosome this means that there is no transmission of the disease from father to son.
X-Linked (type 1)
The defect is on the ‘X' chromosome in the Connexin 32 gene protein at q13.1
Inheritance: autosomal semi-dominant which means that CMT only appears when the mutated proteins in the gene stop communication between the cells.
Clinical signs: hand and foot weakness; early loss of ability to tell the position of hands and feet; no reflexes in hands and feet, but do have reflexes in other areas of the body; hearing loss with some mutations.
Severity is determined by the amount of protein lost from the Connexin 32 gene.
* Females: mild or no symptoms
Nerve conduction shows axonal loss or mild slowing of NCV.
* Males: mild severity
Point mutations producing a mixed neuropathy with demyelination and nerve fibre death.
EMG studies show nerve conduction speed slightly below normal.
* Males: moderate severity
Point Mutations in most areas of Connexin 32 gene protein.
EMG studies show more slowing of nerve conduction speed.
* Males: moderate to severe
Shows deletion of or extra protein in Connexin 32 gene.
- onset under 10 years of age
- more disabling
EMG studies show demyelinating neuropathy with very slow nerve conduction speeds.
Nerve biopsy shows thin myelin sheaths, a few ‘onion bulbs' and less loss of large nerve fibers than in CMT1A.
Genetic testing is available.

Cowchock Syndrome
Gene defect is on the X chromosome at q24-q26.
Inheritance: autosomal recessive, both parents must have the gene defect.
Onset: birth to five years of age.
EMG shows loss of nerve fibers (axons), may show slowing of NCVs in hands, sensory (feeling) nerve fibers very abnormal
Clinical signs: weakness in feet more than hands; loss of sensation; no reflexes; high arched feet and hammertoes; 60% have mental retardation; deafness occurs in most by age of five.
Nerve biopsy shows loss of nerve fibers and regeneration of nerve fibers.
Genetic testing is available.

CMT 1 X-linked (type 2)
Gene defect is on the X Chromosome at the Connexin 32 gene in the p22.2 region
Inheritance: autosomal recessive, both parents must carry the genetic defect.
Onset occurs at less than 10 years of age.
Clinical signs: weakness of feet and hands.
Genetic testing is available.

CMT 1 X-linked (type 3)
Gene defect is on the X Chromosome in the Connexin 32 gene at the q26 region.
Ineritance: autosomal recessive, both parents must carry the genetic defect.
Onset is about the age of 10 years.
Clinical signs: include weakness of hands and feet.
Genetic testing is available.

CMT Type 2
(occurs in approximately 7 per 100,000 population)
This is the axonal or neuronal type in which the nerve fiber itself degenerates and there is an increased frequency of restless leg syndrome.
Genetic studies for all forms of Type 2 are limited to linkage analysis to identify the chromosome affected, the gene has not yet been identified. These studies are only available through specific research projects.

CMT Type 2A
Gene defect is found on Chromosome 1 at p36 but the gene itself has not yet been identified
Inheritance: autosomal dominant in Tunisian families with a 50% chance in each pregnancy of each child having CMT.
Onset: age three to 15 years.
Clinical signs: difficulty walking, climbing stairs and running; weakness in front and back of both feet and both lower legs, with mild sensation loss and loss of reflexes in legs.
EMG shows loss of nerve fibers, slightly slow nerve conduction speed in (median) nerve of hands.
Genetic studies are not available.

CMT Type 2 B
Gene defect is on Chromosome 3q, the gene has not yet been identified.
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset: between 10 and 20 years of age.
EMG studies show loss of nerve fibers (axonal destruction), often with no response from (sural) sensation nerve in legs, normal or near normal nerve conduction speed.
Clinical signs: sensation loss and weakness in both lower limbs worse than upper limbs; tendon reflexes are normal but reduced at ankles; foot ulcers often occur; no pain. Symptoms vary within families from mild to severe.
Genetic studies are not available.

CMT Type 2C
Gene defect: gene and chromosome defect are unknown.
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset: early childhood.
EMG studies show hand (Median) nerve conduction speed greater than 50 metres/sec.
Clinical signs: weakness of hands and feet which may progress to upper limbs, body and face; diaphragm muscle and vocal cord paralysis with altered voice and shortness of breath; loss of or reduced tendon reflexes; sensation loss with no symptoms.
Genetic studies are not available.

CMT Type 2D
Gene defect is on Chromosome 7p14, but the gene is unknown. Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset: 16 to 30 years of age
EMG: loss of nerve fibers (axons), nerve conduction speed normal.
Clinical signs: weakness and sensation loss in arms and legs; no tendon reflexes in arms and reflexes decreased in legs; progression slow over many years.
Genetic studies are not available.

CMT Type 2: Ouvrier Type
Gene defect: unknown.
Inheritance: autosomal recessive, both parents must have the gene defect for a child to have CMT.
Onset: early childhood.
EMG: loss of nerve fibers (axons)
Clinical signs: weakness of both feet and lower legs before arms; mild sensation loss; progression slow; severe foot and hand weakness by 20 years of age.
Genetic testing is not available.

CMT Type 2 recessive
Gene defect: Chromosome 1q21-q21.3, gene unknown.
Ineritance: autosomal recessive, both parents must have gene defect for the child to have CMT …Moroccan family.
Onset: 10 to 20 years of age.
EMG: nerve conduction speed normal, nerve fiber loss with some regeneration.
Nerve biopsy: increased number of large nerve fibers with myelin sheath.
Clinical signs: weakness of both feet and both hands, 60% have weakness upper limbs; progression produces prominent disability; increased tendon reflexes in legs; 80% have high arched feet; 30% have curving of spine both outward and sideways, with upper limb weakness.
Genetic testing is not available.

CMT Type 3 (Dejerine-Sottas)
(CMT Type 3 is now being considered as a variant of CMT Type 1)

CMT Type 3A
Gene defect is on Chromosome 17 with PMP-22 point mutations.
Inheritance: autosomal dominant, often sporadic but with a 50% chance in each pregnancy of each child having CMT.
Onset: in infancy and under three years and is non-progressive.
EMG studies show demyelinating neuropathy with very slow nerve conduction speed.
Nerve biopsy: nerve large in some people, less myelin than normal, long lengths of nerve fibers with loss of myelin sheath.
Clinical signs: scoliosis; delayed walking 15 to 48 months; club foot; poor muscle control in infant; normal speech development; no tendon reflexes; severe sensation loss all limbs; difficulty with balance; eye abnormalities; early high arches; severe lower leg atrophy; hand muscle weakness; claw hand; muscle weakness at birth; muscle cramping and twitching; hearing loss.
Genetic studies not available.

CMT TYPE 3B
Gene defect: point mutations on Chromosome 8q23-24.
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset: infancy.
EMG studies show demylinating neuropathy with nerve conduction speed very slow.
Clinical signs as CMT 3a: weakness of legs and arms; feet and hands weaker than upper limbs; delayed walking and little progression of disease; hearing loss. "Charcot joints" (degeneration of the joints, primarily ankles) occurs.
Genetic studies not available.

CMT Type 3 C
Gene defect is on Chromosome 1q22 with similar genetic makeup of parents producing absence of myelin protein zero gene.
Inheritance: autosomal recessive, both parents must have genetic defect.
Onset: in infancy.
Clinical signs, as CMT 3a: very severe.
Genetic studies are not available.

CMT 4A
Gene defect is on Chromosome 8 q13-q21.1.
Inheritance: autosomal recessive, both parents must have the genetic defect.
Onset: childhood, five years to adolescence in Tunisian families
EMG studies show demyelinating neuropathy, reduced myelin formation, ‘onion bulbs', no myelin outfolding.
Nerve biopsy shows thin myelin sheath, with a reduced number of nerve fibres.
Clinical signs: high arches; delayed walking; rapidly progressive foot, lower leg, hand, forearm weakness. Genetic studies are not available.

CMT Type 4B
Gene defect is on Chromosome 11q22.1
Inheritance: autosomal recessive
Onset: two to four years of age.
EMG studies show demyelinating neuropathy with loss of nerve fibers (axons).
Nerve biopsy shows folded myelin sheaths.
Clinical signs: weakness of all limbs equally; progressive (adults need w/c); facial weakness; sensation loss; no tendon reflexes; high arches with rotation deformity of feet; prominent thick lips.
Genetic studies are not available.

CMT Type 4C
Gene defect is in Chromosome 5q23-q33.
Inheritance: autosomal recessive
Onset: two to five years or adolescence, in Algerian, Dutch and possibly Swedish pedigrees.
EMG studies: moderately slow nerve conduction speed.
Nerve biopsy shows a few ‘onion bulbs', thickening of myelin, severely decreased number of nerve fibres and deterioration of nerve covering (myelin sheath).
Clinical signs: progressive curvature of the spine between three and
nine years of age; high arches; slowly progressive weakness, legs worse than arms; delayed walking up to 30 months; sensation loss; vibration loss; joint position loss; most have no tendon reflexes, no tremor or ataxia; mild walking problems after 15 years disease duration; very slow progression; occasional patient requires wheelchair in 20s to 40s.
Genetic studies are not available.

CMT Type 4D
Gene defect: Chromosome 8q24 (may be related to CMT4A)
Inheritance: autosomal recessive, in gypsies in Lom, Bulgaria, Slovenia, India and Italy, carriers have no symptoms and normal NCVs.
Onset: one to 10 years of age.
EMG: nerve conduction speed very slow, loss of nerve fibers, especially nerve fibers for sensation.
Nerve biopsy: 'onion bulbs' on nerve fibers in children, deterioration of myelin sheath (covering on nerve), loss of nerve fibers.
Clinical signs: difficulty walking; weakness worse in lower limbs than upper; hand weakness occurs at five-20 years of age; tongue atrophy; sensation loss in all lower limbs; 50% have high arched feet; 20% have curved spine; deafness in 30s; disturbance of balance from lesion in ear.

CMT Type 5 aka HMSN Type 5
Axonal CMT with CNS Involvement

Gene defect is unknown.
Inheritance: autosomal dominant with a 50% chance in each pregnancy of each child having CMT.
Onset: before 20 years of age.
EMG studies shows loss of nerve fibers (axons).
Clinical signs: weakness in feet, lower legs, worse than hands and arms; toes ‘flare' instead of curl when Babinski reflex tested; no spasticity of muscles.
Genetic studies are not available.

CMT Type 6 aka HMSN Type 6
CMT with optic atrophy, and hearing loss
Gene defect is unknown.
Inheritance: autosomal dominant, researchers have also found autosomal recessive forms and X-linked forms.
Onset: age seven to 10 years.
EMG studies shows axonal sensory-motor neuropathy.
Clinical signs: severe vision loss; light perception only by age 30; red-green color blindness with other optic atrophies of blue-yellow defects; sensation loss in feet and hands; reduced tendon reflexes; hearing loss.
Genetic studies are not available.

Hereditary Neuropathywith Liability to Pressure Palsies (HNPP)
The location of the genetic abnormality is identical to the area duplicated in CMT1A. PMP-22 protein is increased in the nerves in HNPP. Syndrome has several different variants identifiable with genetic testing.
Gene defect is on Chromosome 17p11.2-p12; 70% to 84% have PMP-22 deletion. Some people with HNPP have a PMP-22 point mutation, some have extra genetic material inserted which usually manifests as the CMT1 + HNPP syndrome.
Inheritance: autosomal dominant, with a 50% chance in each pregnancy of each child having HNPP; 37% of patients have no family history. "Sporadic" cases often show deletions from father's side, rarely from mother's side.
Onset: mid 20s but age range eight to 64 years.
EMG: mild slowing of nerve conduction speed, worse at common pressure sites; carriers with no symptoms have abnormal EMG in childhood with slow nerve conduction speed either of nerves for sensation or motor nerves.
Nerve biopsy shows sausage shapes and folding (tomaculae) of myelin sheath (covering over nerve fiber), segments of nerves demyelinated (deterioration of myelin sheath).
Clinical signs: some people have no symptoms; sudden onset of nerve paralysis after mild injury or compression (40%), after repeated exercise or on awakening (10%), have one to 10 episodes. Recovery is complete in 50%, 9% have severe long-term motor deficit. Often one-sided paralysis with pressure related areas in 62%. Common sites are at the elbow, wrist, knee, neck/shoulder. Signs often at unusual compression sites. Progressive generalized motor-sensory neuropathy may occur without pressure palsies and often occurs in the CMT1 + HNPP syndrome. Normal tendon reflexes (62%); recurrent neuropathy with neuralgia involving many nerves.
Genetic testing is available.

Linda here - As I read all of these different types, many of them listed as saying genetic testing is available, I began to think where is the testing available. So I called Dr. Pestronk, and he told me that some types are tested only for research but that there are four places in the U.S. that test various types of CMT. I'll list some of them briefly here and follow up next time with more. Your GP will call them to find out what they need and how to send it.
Athena Diagnostics - tests for 1A, 1B, 1X and HNPP. Cost is $1,195 for a complete test; 1A and 1B only $795 and $495 each - Tel: (508)756-2886
Boston University - CMT 1B only- $950. Dr. Aubrey Milunsky, Dir., Centre of Human Genetics - Tel: (617)638-7083
Baylor University - CMT1A prenatally and otherwise - Tel: (713)798-4984

N.B. Note that this article was written in 1999.