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Supporting people affected by Charcot-Marie-Tooth disease.

Classification

It is beyond the scope of this websote to describe all the 80+ causative genes behind CMT. This page aims to describe briefly the current understanding of the genetic classification of the commoner types of the condition.

Classification of CMT

The key point to remember is that there are two main forms of CMT:

  • Demyelinating (CMT1) – affects the myelin sheath insulating and nourishing the nerve’s axon.
  • Axonal (CMT2) – directly affects the axon.
Demyelinating CMT (CMT1)

CMT1 is the most common form of CMT (six out of ten people with CMT will have CMT1A), affecting the nerve’s insulating myelin sheath. Some forms of CMT1 have an earlier age of onset and these forms used to be called HMSN3 in the old classification but are now more commonly referred to as severe CMT1. Two of these forms are sometimes referred to as Dejerine Sottas disease (DSD) and Congenital Hypomyelinating Neuropathy (CHN) but these are both forms of CMT1. Autosomal dominant CMT1 (AD CMT1) is much more common than autosomal recessive CMT1 (AR CMT1, more commonly called CMT4). Generally, people with AR CMT1 / CMT4 have an earlier onset and more severe form of CMT.

AD CMT1

  • CMT1A: The Chromosome 17 duplication containing the peripheral myelin protein 22 gene (PMP-22), is responsible for six out of ten cases of CMT1 in the UK. CMT1A is the ‘classical’ form of CMT. People usually develop symptoms in the first 20 years of life, have a very slowly progressive condition and a normal lifespan. A deletion of the same part of chromosome 17 causes hereditary neuropathy with liability to pressure palsies (HNPP). Mutations in PMP-22 can also cause a more severe form of CMT1 (DSD and CHN in old literature).
  • CMT1B: Mutations in MPZ (myelin protein zero) are responsible for CMT1B. This form of CMT is the second commonest form of AD CMT1. It can be just like ‘classical’ CMT but onset is sometimes earlier and the condition more severe. Mutations in MPZ can also cause a late-onset mild form of CMT2.
Axonal CMT (CMT2)

CMT2 is not as common as CMT1, but has similar symptoms. Rather than damaging the nerves’ insulating myelin sheath, CMT2 affects the axon. Because of this CMT2 is also known as ‘axonal CMT’. Symptoms are often first noticed between the ages of 10 and 20 but CMT2 can start earlier or later. Like CMT1, autosomal dominant CMT2 (AD CMT2) is much more common than autosomal recessive CMT2 (AR CMT2), which is very rare.

AD CMT2

  • CMT2A: Mutations in Mitofusin 2 (MFN2) are responsible for about one in five cases of AD CMT2. This usually presents in a more severe form than the ‘classical’ CMT, commonly in the first decade of life. People with CMT2A can be severely affected – with some needing wheelchairs – while others are more mildly affected. There is therefore a wide spectrum of disease severity in CMT2A.

AR CMT2

  • The gene mutations that cause AR CMT2 are all very rare
X-Linked CMT

CMTX is a variation of CMT1 and CMT2. It is called ‘X’ because the genes that cause this form of CMT are carried on the X chromosome. It usually affects men much more severely than women because a man has only one X chromosome and women have two.

CMTX1

CMTX1: Mutations in GJB1 (the protein from this gene is connexin 32) cause the commonest form of x-linked CMT. This is the second-commonest form of CMT, affecting about 10% of all people with the condition. This form usually affects males more severely than females. Males usually present in the first decade of life and on average have a more severe form of CMT than the ‘classical’ form. They still have a normal lifespan and rarely need a wheelchair. Their nerve conduction studies look like CMT1. Females may have no symptoms (but often have subtle signs when examined) or they may be mildly affected. The nerve conduction studies in females look like CMT2.

DI-CMT

DI stands for ‘dominant intermediate’. This form of CMT is rare and usually has similar symptoms to the common versions of AD CMT1 and AD CMT2. The reason it is called intermediate is that both the myelin sheath and the axon are damaged equally.

For both CMT1 and CMT2 there are many different subtypes and you may hear about CMT1A or CMT2A, for example. These are all different genetic variations of the main types.

 

More detail:

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. CMT Type 1 accounts for more than two-thirds of all cases of CMT.

Type 1A

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.

Type 1B
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.)

Type 1C
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.

Type 1D
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.

Type 1F
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.

Type 1X
This second most common of form of CMT, accounting for 10-16 percent of all cases is found on the X Chromosome, one of 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.

 

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.

Type 2A
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. This type of CMT is often severe and can include optic atrophy.

Type 2B
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.

Type 2C
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.

Type 2D
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.

Type 2E
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.

Type 4A
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.

Type 4B
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
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.

Type 4D
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.

Type 4F
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.

 

Information updated from www.cmtausa.org with thanks

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