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 is also comprised of motor and sensory nerve fibers, and since CMT affects the peripheral nerves, it 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), which is wrapped in insulation (a sheath called myelin). 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.
All forms of CMT are either demyelinating or axonal in nature. Since CMT is a multi-gene disorder, there are many different defective genes which cause the disorder. Since 1991, more than 30 different genes causing CMT have been identified and the loci are known for at least another ten causes. The ones that have been identified to date are:
CMT Type 1
With the exception of Type 1X, which is inherited through the X Chromosome, CMT Type 1 is inherited in an autosomal dominant pattern. (See inheritance.) CMT Type 1 accounts for more than two-thirds of all cases of CMT. (More about CMT Type 1.)
This is the most common form of CMT, comprising at least 60 percent of all patients with CMT Type 1. The disorder is caused by a duplication of the PMP22 gene on Chromosome 17. Instead of having two copies of the gene (one of each paired chromosome), 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. It is inherited in an autosomal dominant fashion.
CMT1A usually presents with a typical CMT phenotype (clinical presentation). Patients are slow runners in childhood, develop high arches, hammertoes and often require orthotics (braces) for ankle support. Varying degrees of hand weakness occur, often appearing as much as ten years after foot and leg problems. Problems with balance because of ankle weakness and loss of proprioception are common. Most patients remain ambulatory throughout life and life expectancy is normal.
This type is caused by a defect of the MPZ gene on chromosome 1. Again, MPZ is peripheral myelin protein, but its role is not known. Type 1B is an autosomal dominant disorder. Patients with 1B have a somewhat typical phenotype, but often with more pronounced calf wasting. There is a wide range of severity within Type 1B, from very severe forms such as Dejerine-Sottas (infantile onset) to milder cases with onset much later in life. (More than one type of CMT may be referred to as Dejerine-Sottas since the term refers to an age of onset of less than three years rather than to a unique genetic defect.)
Researchers at the University of Washington have recently identified the locus of Type 1C as Chromosome 16, the LITAF/SIMPLE gene. Type 1C is also autosomal dominant in inheritance. There is limited clinical information on patients with 1C, but they develop distal weakness, atrophy, and sensory loss and have slow nerve conduction velocity scores.
This type is caused by an early growth response protein 2, known as ERG2, found on Chromosome 10. Inheritance is autosomal dominant. Most cases of 1D are severe, such as Dejerine-Sottas, while a few have milder phenotypes presenting later in life.
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 second most common of form of CMT, accounting for 10-16 percent of all cases is found on the X Chromosome, one of the sex chromosomes. The flaw is caused by a gap junction beta 1 protein connected to connexin 32. Typically, this form has onset in adolescence or childhood and often affects males more severely than females. An affected male with CMT1X cannot pass the defect to his son, but will pass it to all his daughters. An affected female has a 50% chance of passing the mutation to either her sons or her daughters.
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.
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.
CMT Type 3
Type 3 is a particularly severe variant. The term Dejerine-Sottas syndrome (DSS) is used to describe patients who are severely disabled and develop CMT in infancy. This term was coined before the genetic causes of CMT were identified. As a result, the usage of this term is somewhat confusing. Dejerine-Sottas was originally thought to be a severe and disabling neuropathy beginning in infancy with an autosomal recessive inheritance pattern. Recently, it has been shown that DSS patients also have autosomal dominant mutations of PMP22, MPZ, EGR2 and even PRX and GDAP. Most patients with DSS have extremely slow nerve conduction velocities. Most children with DSN have severe demyelination while others show predominantly axonal loss when sural nerve biopsies are done. Currently, the term Dejerine-Sottas is used to define patients who have onset by 3 years of age, delayed motor milestones, and severe motor, sensory and skeletal defects.
Congenital hypomyelination (CH) is a term originally used to describe peripheral nerves that were so abnormal that they suggested a developmental failure of the peripheral nervous system myelination. Patients with CH were hypotonic within the first year of life, had developmental delays in walking and had swallowing or respiratory difficulties. Some patients with CH were considered “floppy” infants. It is difficult to distinguish between DSS and CH since both have severe pathological changes on sural nerve biopsies and both have very slow nerve conduction velocities.
CMT Type 4
All Type 4 instances of CMT are inherited in an autosomal recessive pattern and are considered rare. They have various phenotypical presentations but are more severe than autosomal dominantly inherited disorders. These disorders often have systemic symptoms, such as cataracts and deafness. CMT 4A and B are demyelinating and 4C is axonal.
CMT Type 4 is linked to Chromosome 8 and is caused by mutations in the GDAP 1 protein, of unknown function. This form was first described in four families in Tunisia who were highly inbred. Clincial onset began at age 2 with delayed developmental milestones of sitting or walking. Many patients are wheelchair dependent by the end of the first decade of life. Hoarse voice and vocal cord paresis have been reported.
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.
Type 4C is a childhood onset form of hereditary motor and sensory neuropathy (HSMN) with early onset scoliosis. The protein defect defines a new family of unknown function.
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.