People affected by CMT usually present significant family history that can be used to detect the underlying mutations. The first signs generally begin to appear in the first two decades of life, but in certain cases they can even occur in the early thirties or forties. Muscle tissue wasting is undoubtedly one of the first signs to emerge, starting from the distal limbs, especially the lower extremities which give to the subjects the classic “stork legs” or “inverted champagne bottle” appearance. These signs are soon followed by foot drop, hammer (or curled) toes, and high or flat arched feet, which are usually associated with this disorder. When wasting and weakness begin to involve hands, the patient starts experiencing the typical symptoms of hand weakness like poor finger control, difficult handwriting and clumsiness in manipulating small sized objects. All these symptoms can be followed by tremor, which appears as further consequence of progressive muscle weakness.

In the later stages of the disorder, loss of sensation can also be observed, generally accompanied by problems involving breathing, hearing, vision and neck or shoulder muscles. These can then lead to further complications such as scoliosis and hip dysplasia. Gastrointestinal complications can emerge as well, which are usually coupled with difficulty in chewing and swallowing.

Pain is another classic sign of CMT, due to postural changes, skeletal deformations, muscular fatigue, cramps and spasms, and is usually coupled with painful and spasmodic muscular contractions and numbness. In the most severe cases, pain can become neuropathic and might seriously affect the patient’s daily life.

CMT can be detected by using different approaches, such as observing physical symptoms, studying the measurements of nerve impulse speeds or using DNA testing.
Observing the physical symptoms is definitely the first thing to do while diagnosing CMT, especially by taking into consideration key signs such as lower legs weakness, foot drop and foot deformities. Physical symptoms are strongly indicative for the presence of CMT, but cannot be conclusive for a final diagnosis.

Imagining studies, like high-resolution ultrasonography and magnetic resonance imaging, can give a deeper prospective to physicians, by providing clear images of peripheral neuronal structures such as median or vagus nerves. These methods can be extremely informative for the CMT diagnosis, especially when coupled with procedures to measure nerve signal conduction like electromyography. Histological methodologies, as well as nerve biopsy, are also frequently used, to better observe neuronal abnormalities such as bulb formations, axonal degenerations or demyelination processes.

In any case, the most conclusive evidence is undoubtedly DNA testing, which provides with the exact DNA sequences of the genes involved in this disorder. There are many genetic markers available, for the major genes connected with CMT, such as PMP22, MPZ and GDAP1, which can also be used in family history studies. It is important to notice that the lack of a family history does not rule out CMT, but can rule out other causes of neuropathy, like exposure to drugs and chemicals affecting the nervous system.

At the moment, there is no standard treatment for CMT to reverse or slow its progress. Therefore, patients can only get a symptomatic treatment aimed at mitigating the signs.
It is very important for the subjects to try to maintain movement, muscle strength and flexibility, in the attempt of delaying the CMT debilitative effects. Thus, the organization of a physical therapy plan is paramount, and this has to be done with the help of a physiotherapist. The specialist might also indicate the use of orthoses, especially to address physical abnormalities and improve patient’s balance. In the most severe cases, instead, surgery is highly advised to address physical deformities and try to improve patient’s quality of life.

The prognosis of CMT varies from type to type, and is mostly determined by the clinical severity of the type concerned. Anyways, it is possible to observe a slow and progressive peripheral neuropathy which eventually results in disability, weakness and deformities of distal muscles. The most usual complication consists of the loss of protective sensation at the ends of all four limbs, which leads to skin breakdown, burns, ulcers or bony deformities. Patients affected by any type of this disorder are advised to get genetic counseling, to attest the risk of having children with the same disease and get help to make informed decisions on their pregnancy [19] [20].

Charcot Marie Tooth disease is caused by a number of mutations in the genes of key neuronal proteins which affect both axon and myelin. This provokes the devastating consequences characterizing this disorder.

For example, the most common mutation causing CMT, which affects from 70 to 80% of the cases, is a duplication of a large section of the short arm of chromosome 17. The affected section contains the gene PMP22 decoding the peripheral myelin protein 22, a glycoprotein mainly expressed in the Schwann cells and representing one of the major components of the compact myelin in the peripheral nervous system [6]. This mutation causes severe consequences to myelin structure and to the efficiency of neuronal signal transmission.

Another example is given by the mutations occurring in the gene MFN2, which encodes the mitochondrial protein mitofusin-2 [7] [8]. Mitofusin-2 is a GTPase involved in the maintenance and the operation of the mitochondrial network, which is mainly characterized by the classic movement of mitochondria down the nerve cell axon to provide the distal axon elements, like synapses, with the energy they need to work in a proper manner. When MFN2 is mutated, long peripheral axon degeneration occurs and mitochondria form numerous clusters unable to travel down the axon, thus preventing synapses from effectively transmitting the nervous signals [9]. The exact mechanism of how MFN2 mutations cause axon degeneration is not known, but substantial experimental data suggest that the impaired mitochondria movement towards the neuron ends might play an important role in it [10].

Many other mutations interest the Schawnn cells and how they communicate with neurons during survival and differentiation. These disrupted signals [11] result in the appearance of abnormal axon structures and functions, as well as the already mentioned axon degeneration [1].

As previously said, CMT is one of the most common inherited neuronal disorders affecting the peripheral neuronal system. In the United Stated, CMT has a particularly high prevalence, since it affects 1 over 2500 persons, for an estimated total number of people affected of around 125000. The prevalence is much lower in other countries. For example, in Japan prevalence is of 10,8 cases every 100,000 people, while in Italy it is of 17,5 cases in 100,000 people. The incidence, instead, varies according to the subtype considered. For example, CMT1 has an incidence of 15 cases every 100,000 people, while CMT2 has an incidence of 7 cases every 100,000 people.

CTM includes many subtypes, caused by different mutations but with similar clinical presentations [12], which can be defined as either demyelinating disorders (affecting myelin) or axonal disorders (affecting the axon). The demyelinating disorders include CMT1, undoubtedly the most common type of CMT, caused by the mutations in the already mentioned PMP22 gene. The mutations result in the production of an abnormal and unstable myelin which spontaneously breaks down, in a process of demyelination provoking a uniform slowing of conduction velocity. In response to this demyelination, the Schwann cells begin to proliferate and form arrays of myelin, in what can be defined as a process of remyelination. Repeated cycles of demyelination and remyelination cause the formation of thick myelin layers around the peripheral axons appearing like onion bulbs, which seriously impair nervous signal transmission. Other examples of demyelinating disorders are CMT3, also known as Dejerine-Sottas disease which is much more severe than CTM1, and CTM4 [13] [14]. Pain and temperature sensations are not affected by these types of neuropathy, because their signals are carried by unmyelinated neurons. An example of axonal disorder [15] [16] [17] [18], instead, is given by CMT2, which is caused by a direct degeneration and death of axons.

Since CMT is an inherited disease, there are no preventive measures to avoid its inevitable progression. In any case, patients are urged to make regular follow-up visits to check complications and avoid permanent functional limitations [21].

Previously defined as a subtype of muscular dystrophy [1], Charcot Marie Tooth disease (CMT) includes numerous inherited neuropathies with no metabolic derangement [2] [3] [4] [5], and all of them characterized by a progressive loss of muscle tissue and touch sensation of the body parts involved. Since it was first described back in the second half of the nineteenth century, CMT has been divided in many different subtypes on the basis of pathological and physiological criteria. Affecting 1 in 2500 people [1] in US, CMT is now considered one of the most common inherited disorders affecting human beings.

Charcot Marie Tooth disease (CTM) is one of the most common and heterogeneous group of inherited disorders which affects the peripheral nervous system in different parts of the bodies, all of them characterized by a progressive loss of muscle tissue and touch sensation of the parts involved. Since it was first discovered, CMT has been divided in many different subtypes on the basis of pathological and physiological criteria. This disorder is caused by a number of mutations in the genes of key neuronal proteins which affect both axon and myelin. This provokes the devastating consequences characterizing CMT, mainly resulting in the appearance of abnormal axon structures and functions, and the occurrence of axon degeneration.

The first signs generally begin to appear in the first two decades of life, but in certain cases they can even occur in the early thirties or forties. Among the main signs of CMT there are muscle tissue wasting, loss of sensation and pain. At the moment, there is no standard treatment or prevention strategy to reverse or slow CMT progress. Therefore, patients can only get a symptomatic treatment aimed at mitigating the signs.

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