Cross-section of a myelinated neuron.
The nervous system consists of motor neurons and sensory neurons. One set of nerves carries messages from the brain outward to the rest of the body and one brings messages from the extremities back to the brain. Messages that travel from the brain down the spinal cord, through the lower motor neurons (such as the sciatic nerve of the leg) to the muscles of the body are part of the motor neuron circuitry. Messages that travel upward from the sensory input to the spinal cord and finally the brain are sent by sensory neurons. The peripheral nervous system also comprises motor and sensory nerve fibers, and since CMT affects the peripheral nerves, it usually results in both motor symptoms (weakness and muscle wasting) and sensory symptoms (numbness).
The peripheral nerves are often described as being like electrical wires, with an inner core (the axon) that is wrapped in insulation (the myelin sheath). When the myelin is damaged (Type 1 CMT), the nerve impulses are conducted more slowly than normal. If the axon itself is damaged (Type 2), the speed of nerve conduction is almost normal, but the strength of the signal is reduced.
CMT forms are usually either demyelinating or axonal in nature, though intermediate forms also exist. Since CMT is a multi-gene disorder, there are many different genes that cause the disorder when mutated. Since 1991, more than 100 different genes causing CMT have been identified and the list continues to grow. CMT can be divided into types and subtypes. The types are the clinical pictures of CMT (CMT type 1, 2, 4, X, etc.), usually defined by inheritance pattern and nerve conductions. Subtypes (CMT1A, 2B, 4C, X1, etc.) are given only when the genetic cause is known. Each subtype corresponds to a gene: Every person with CMT2B has a mutation in the RAB7 gene and everyone with CMT4C has two mutations in the SH3TC2 gene.
CMT Type 1
CMT Type 1 (CMT1) is defined as an autosomal dominant (see inheritance.) demyelinating form of CMT. CMT1 accounts for about 55 percent of all cases of CMT. (More about CMT Type 1:
This is the most common form of CMT, comprising around 66 percent of all patients with CMT1. The disorder is caused by a duplication of the PMP22
gene on Chromosome 17. Instead of having two copies of the gene (one from each parent), there are three copies, two on one chromosome and one on the other. PMP22 is a peripheral myelin protein, but its exact function in causing CMT is still not known. CMT1A usually presents with a typical CMT phenotype (clinical presentation). Usually, people with CMT1A are slow runners in childhood, develop high arches and hammertoes and often require orthotics (braces) for ankle support. Varying degrees of hand weakness occur, often appearing as much as 10 years after foot and leg problems. Problems with balance because of ankle weakness and loss of proprioception (the brain’s ability to know where the limbs are in space) are common. Most patients (95 percent) remain ambulatory throughout their lives and life expectancy is normal.
Research on CMT Type 1A
CMT1B is caused by mutations in the MPZ, or peripheral myelin protein, gene. There is a wide range of severity within CMT1B, from very severe, infantile onset to milder cases with onset much later in life. About 40 percent of people with CMT1B have an infantile onset with delayed walking (after 15 months), and development of symptoms before 5 years of age. Hip dysplasia and optic nerve atrophy have been observed in this group (though hip dysplasia may happen in up to 20 percent of kids with CMT), and scoliosis in about a third of people. People with early-onset CMT1B tend to have very slow nerve conduction velocities, with speeds <15 m/s in the arms (normal >50 m/s). A minority (7 percent) of people with this disease-causing variant in the MPZ gene have a childhood onset, with symptoms between 6 and 20 years of age. This group tends to have slow nerve conductions, between 15 and 25 m/s. The remainder of people with CMT1B have an adult onset, with symptoms tending to begin after age 40 and a comparatively milder presentation. Their nerve conduction studies tend to be in the intermediate range of between 35 and 45 m/s.
Research on CMT Type 1B
CMT1C is caused by disease-causing variants in the LITAF
gene, also previously referred to as SIMPLE
. This is a rare form of CMT, affecting fewer than 1 percent of people who have the disease. Presentation is similar to CMT1A, with onset between the first and third decades, and weakness in the feet and hands, atrophy, and sensory loss and slow nerve conduction velocities (16-25 m/s).
CMT Type 1D is caused by mutations in a gene on chromosome 10 called EGR2, which codes for the early growth response protein 2. CMT1D is very rare and causes less than 1 percent of cases of CMT. Most people with CMT1D show severe symptoms in the first decade of life, including delayed motor milestones and nerve conduction velocities of 10 m/s or less (sometimes referred to as Dejerine Sottas syndrome). A few cases of CMT1D have milder symptoms that appear later in life. Other symptoms may include cranial nerve dysfunction and respiratory difficulties. There have been extremely rare reports of EGR2 causing an autosomal recessive form of CMT, termed CMT4E.
Point mutations in the PMP22 gene cause CMT1E. People with CMT1E tend to have earlier onset and more severe symptoms than those with CMT1A, but this may vary. Conduction velocities in patients tend to be markedly reduced, usually under 10 m/s (normal in the arms is >50 m/s). Children often present within the first two years of life with delayed walking. Many people do progress to needing ambulation aids, such as a walker or a wheelchair, earlier than those with CMT1A. CMT1E is a rare form of CMT, accounting for approximately one percent of people with genetically confirmed CMT.
Type 1F accounts for a very small percentage of cases. It is an autosomal dominant form of CMT in which the defect is on Chromosome 8 and the neurofilament light chain protein.
This is the second most common form of CMT, accounting for 10 – 16 percent of all cases. The gene that causes CMT1X is GJB1
(previously referred to as Cx32
), and the protein is called connexin 32. This gene is found on the X chromosome, one of the sex chromosomes. Females have two X chromosomes (XX) and males have an X and a Y chromosome (XY). Because males only have one copy of the X chromosome, they only have one copy of this gene. If there is a variant in the gene that causes it not to work, males do not have a “backup” copy to help make connexin 32 protein. Females have an extra copy of the gene. Females tend to be less severely affected than the males in their family, but 90 percent have some symptoms. About two-thirds of affected women have symptoms in the mild range and one-third have symptoms in the moderate range. Most males have moderate to severe neuropathy as they age.
The CMT genes found on the X chromosome have a different form of inheritance, called X-linked inheritance. In every pregnancy, the female passes down one copy of a chromosome pair and her partner passes down the other copy for the pair. In order for a child to be born female, she must inherit the X chromosome from her dad. In order for a child to be born male, he must inherit the Y chromosome from his dad. A woman will pass down one or the other of her two X chromosomes in every pregnancy. Each child of a woman affected with CMT1X has a 50/50 risk of inheriting the condition, no matter the sex of the child. A man affected with CMT1X will pass it on to ALL of his daughters (since they inherit his X chromosome with the GJB1 gene variant), but NONE of his sons (who inherit the Y chromosome which does not have a GJB1 gene). The sex of the parent or the child ONLY matters in X-linked inheritance.
Research on CMT Type 1X
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)
HNPP is also inherited in an autosomal dominant pattern and is also located on Chromosome 17 at the PMP 22 gene, as is Type 1A. The difference is that there is a deletion rather than a duplication at the gene site. Clinically, HNPP differs from CMT in that patients with HNPP typically have transient episodes of weakness or sensory loss, which can last from hours to days. Thickening of myelin is the hallmark of HNPP. (See More about HNPP.)
CMT Type 2
CMT Type 2 represents axonal forms that are dominantly inherited and make up about one-third of all dominant CMT cases. The clinical presentation is similar to Type 1: distal weakness, muscle atrophy, sensory loss and foot deformities. Patients with Type 2 have a wider age range for onset of the disorder and more variation in degree of disability. They are slightly more likely to maintain their deep tendon reflexes. (More about CMT Type 2:
The defect causing CMT 2A is found on chromosome 1p36 at the MFN2 gene. This gene is mutated and is involved in the fusion of mitochondria, the metabolic engines of the cells.
Research on CMT Type 2A
Type 2B is characterized by severe ulceration problems and the defect is located on chromosome 3, the RAB 7 protein. CMT 2B is predominantly a sensory disorder and there is some thought that it is not really CMT, but a pure sensory neuropathy.
This type is a very rare form in which patients may have diaphragm or vocal cord paresis in addition to the other problems of CMT. Linkage to chromosome 12 has been found.
The CMT 2D locus is on chromosome 7p14 and the genetic cause has been identified as mutations in the glycyl RNA synthetase gene. CMT 2D is a confusing disorder because some patients have sensorimotor neuropathies, while others have only motor symptoms.
CMT type 2E has been established with linkage to chromosome 8p21 and studies have identified mutations in the neurofilament light gene.
Research on CMT Type 2E
CMT type 2K (CMT2K) is caused by dominantly inherited mutations in the GDAP1
gene (as opposed to CMT4A, which is inherited in a recessive manner). About 25% of people with mutations in GDAP1 have CMT2K, and 75% have the recessive CMT4A (two mutations in the gene). Symptom onset varies, with about ¼ of people having symptoms before age 10 years, 41% between 10 and 30 years, 20% over 30 years, and 14% asymptomatic after 50 years of age. Less than 10% of people with CMT2K need a wheelchair full-time.
CMT2O is caused by disease-causing variants in the DYNC1H1
gene. This is usually a pure motor form of CMT, with little to no sensory symptoms, with axonal nerve conduction studies. So far, only one variant in this gene has been found to cause CMT2O (c.917A>G, p.His306Arg). Other variants in this gene have been associated with a variety of conditions, some similar to CMT (spinal muscular atrophy with lower extremity predominance (SMA-LED) – lower limb weakness and pes cavus, scoliosis, hip weakness), and some less similar (complicated hereditary spastic paraplegia (cHSP), and malformations of cortical development (MCD) – both which include intellectual impairment).
CMT type 2P (CMT2P) is a rare form of CMT, caused by mutations in the LRSAM1
gene. There have only been a handful of reports of this type in the literature, so more research is needed to understand the range of presentation for people with this type of CMT. The clinical phenotype can be summarized as a relatively mild, very slowly progressive axonal neuropathy with age of onset in the second or third decade of life. Most people after age 30 years have some motor symptoms and pes cavus. There are a couple of reports of fasciculations, or involuntary muscle twitches, in the legs. There are several reports of erectile dysfunction. People may have an elevated serum creatine kinase (CK) level, a measure of leaky muscles (not commonly elevated in CMT).
CMT 2S was first discovered by Dr. Ellen Cottenie in 2014 (http://www.cell.com/ajhg/fulltext/S0002-9297(14)00424-8
). After publication of her article, it was officially registered in the genetic database. CMT 2S is caused by a mutation in the IGHMBP2 gene. IGHMBP2 gene mutations can present with two different phenotypes: 1) the severe SMARD1 (Spinal Muscular Atrophy associated with Respiratory Distress) or 2) the milder CMT2S. Both are rare and recessive in nature. Depending on the specific mutations, patients either have SMARD1, caused by autosomal recessive mutations in the IGHMBP2 gene (which is not related to the myelin protein MBP), or they have CMT2S, which results in slowly progressive weakness, wasting, and sensory loss with an axonal neuropathy typical of CMT2, but without significant respiratory compromise.
CMT2Z stems from disease-causing variants in MORC2. Some people present with generalized weakness in infancy while others present with adult-onset weakness that may include proximal muscles and sensory loss. Many people’s first symptom is cramping in the legs. This form of CMT is length-dependent (meaning that it affects the nerves farthest from the spine first and then travels up), as is typical for CMT, but over decades it progresses to muscles above the knees and elbows, including the hip muscles, deltoids and neck muscles. People with CMT2Z may require progressive ambulation aids over time, with most needing a wheelchair around the fifth decade. This may end up being a very common form of axonal CMT, but because it was only associated with CMT in 2016, it will take some time to see what proportion of the population has CMT2Z. This gene also seems to have a high new mutation rate, with one paper estimating that up to 75 percent of people are the first in their families with disease-causing variants in MORC2.
CMT Type 3
Type 3 is a historical term, also known as Dejerine Sottas syndrome (DSS). This was used to describe people with early onset, severe CMT, usually recessive and usually markedly demyelinating (nerve conduction velocities <10 m/s, with normal being >50 m/s in the arms). Both CMT3 and DSS were coined before genetic causes of CMT were identified. Now, with genetic testing, most of these types of CMT are being renamed to a more appropriate term based on the genetics. Some people still use the term DSS as a descriptor, but CMT3 is almost never used.
CMT Type 4
All Type 4 instances of CMT are inherited in an autosomal recessive pattern (see inheritance) and are rare in the United States (~5% of cases). They have various presentations, with some being mild and some severe. These disorders may also have symptoms in other areas of the body, such as cataracts and deafness.
Research on CMT Type 4
CMT Type 4A (CMT4A) is caused by mutations in the GDAP1 gene. This gene has been found to cause CMT4A (recessive, demyelinating, axonal or intermediate CMT – about 75% of people with GDAP1
mutations), and CMT2K (dominant axonal CMT – about 25% of people with GDAP1
mutations). People with CMT4A have onset of symptoms in the first two decades of life, most before age 10 years. Symptoms affect both lower and upper limbs, including muscle wasting and contractures, and delayed milestones such as sitting and walking. Most people need walking assistance, such as AFOs, canes or walkers, by 30 years of age, and about 75% use a wheelchair after 30 years. As disease progresses, a hoarse voice can develop and vocal cord paresis have been reported. Life expectancy and intelligence are not affected.
The genetic location for the defect causing Type 4B is on chromosome 11 and presents with focally folded myelin sheaths in nerve biopsies. Affected patients become symptomatic early in life, with an average age of onset at 34 months. Unlike most types of CMT, both proximal and distal weakness is common.
CMT Type 4C (CMT4C) is caused by mutations in SH3TC2
and has a wide variability of severity. This type of CMT involves childhood onset of sensory and motor neuropathy in the lower limbs and high arched or flat feet. Patients often have mild difficulty with walking, and some may need a wheelchair. Scoliosis is almost always present, usually onset in the first two decades. The onset of neuropathy symptoms range, some beginning in the first decade of life, and others do not onset until adulthood. Lower limb and upper limb weakness is common, beginning towards the hands and feet and sometimes extending above the elbows and knees. Hearing loss, vocal cord involvement, and facial paresis have been reported. This is a demyelinating form of CMT, with conductions usually ranging between 16 and 36 m/s in the arms.
This form was first described as a separate disorder with linkage to Chromosome 8 in a Gypsy population with autosomal recessive inheritance. The clinical features included distal weakness, muscle wasting and sensory loss, foot and hand deformities and loss of deep tendon reflexes. Deafness is always found in these patients and occurs by the third decade. Nerve conduction is severely reduced in younger patients and completely unattainable after age 15.
CMT type 4F is a severe form of recessive CMT that has been defined in a large Lebanese family with mutations in the PRX gene on Chromosome 19. Nerve conduction studies are markedly slow and onion bulb formations are observed in nerve biopsies.
CMT4J is caused by mutations in a gene called FIG4, which is located on chromosome 6. This is a rare form of CMT that wasn’t identified until 2007. Because not many people have this form, our understanding of how it progresses is limited. Symptoms and age of onset are variable; some people have a classic presentation, while others have a slowly progressive neuropathy with more severe changes later in adulthood. CMT4J causes intermediate to slow nerve conductions due to changes in the myelin, the sheath around the nerve “wire.” It is an autosomal recessive form of CMT (CMT4), which means an individual has to have a mutation in each copy of the gene (one from each parent) in order to have symptoms. Not all changes in FIG4 cause disease, however. If one of an individual’s two mutations is benign, he or she would not have CMT4J.
What is Roussy-Lévy Syndrome?
Roussy-Lévy does not describe a specific type of CMT, but rather an individual’s symptoms. Roussy- Lévy Syndrome is used to describe a phenotype (or expression of symptoms) that includes high arches, loss of reflexes, distal limb weakness, tremor in the upper limbs, distal sensory loss and gait ataxia (lack of coordination), probably due to the sensory symptoms. This can also be associated with a form of scoliosis called kyphosis. Many people with CMT can have this clustering of symptoms: It really isn’t exclusive to any one type, but the key clinical finding is CMT with a tremor. It doesn’t help define what type of CMT a person has, although it does appear to happen more commonly with demyelinating forms of CMT such as CMT1A and CMT1B. There isn’t a lot of information about Roussy-Lévy Syndrome because it is not a specific disorder and the term isn’t is not really used much anymore (like Dejerine-Sottas Syndrome). To better understand and manage Roussy-Lévy, please consult a CMT expert neurologist and/or genetic counselor.