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.

• Respiratory Disorders

  Akiba Y, Kimura T, Kitaoka T, et al. (1996) [Respiratory disorders in type-1 hereditary motor and sensory neuropathy]. Nihon Kyobu Shikkan Gakkai Zasshi 34:850–855 PubMed Google Scholar 3. [doi.org]

• Acrocyanosis

  Other common symptoms and signs include hand tremors, muscle cramps and acrocyanosis. It may be possible to palpate enlarged and excessively firm nerves. [patient.info]

• Hearing Impairment

  In rare cases, sensory loss can include gradual hearing impairment and sometimes deafness. [mda.org]

  Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet. 2001; 10 :947–52. [ PubMed : 11309368 ] Luigetti M, Fabrizi GM, Taioli F, Del Grande A, Lo Monaco M. [ncbi.nlm.nih.gov]

• Foot Deformity

  Common clinical manifestations of CMTX1 disease, as in other forms of Charcot-Marie-Tooth (CMT) disease, are distal muscle wasting and weakness, hyporeflexia, distal sensory disturbance, and foot deformities. [ncbi.nlm.nih.gov]

  Surgery Although surgery can’t help with loss of sensation or muscle weakness, it can: Help stabilize foot deformities. Reduce pain. Improve walking ability for people who have severe foot deformities caused by CMT. [gillettechildrens.org]

  The foot deformities and symptoms related to CMT are typically progressive - they tend to worsen over time. However, the rate at which they worsen can vary greatly. [footeducation.com]

• Muscular Atrophy

  atrophy Peroneal muscular atrophy Charcot-Marie-Tooth disease、C-M-T [wikidata.org]

  Charcot-Marie-Tooth, type II, or the neuronal type of peroneal muscular atrophy); and distal hereditary motor neuronopathy (formerly known as Charcot-Marie-Tooth, type III, the spinal type of peroneal muscular atrophy, or distal spinal muscular atrophy [medical-dictionary.thefreedictionary.com]

  IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. [ncbi.nlm.nih.gov]

  atrophy (axonal type) (hypertrophic type), Roussy-Lévy syndrome [orphananesthesia.eu]

• Leg Weakness

  CMT is usually first noticed when someone develops lower leg weakness and foot deformities such as foot drop, hammertoes and high arches, but that alone will not lead to diagnosis. [web.archive.org]

  Physical therapy and orthotics in combination help improve efficiency, function, and safety with ambulation and other activities, as foot drop and leg weakness are major components of disability in patients with hereditary neuropathies. [massgeneral.org]

  The combination of a foot deformity and lower leg weakness is often the first sign of CMT. A specialist called a neurologist may diagnose CMT after doing a complete neurological exam and asking about your family history. [choc.org]

  Diagnosis The combination of a foot deformity and lower leg weakness is often the first sign of CMT. A specialist called a neurologist may diagnose CMT after doing a complete neurological exam and asking about your family history. [columbianeurology.org]

  CMT is first noticed when someone develops lower leg weakness and foot deformities such as foot drop, hammertoes and high arches. But signs alone do not lead to diagnosis. Patients must be referred to a neurologist. [crystalinks.com]

• Myopathy

  Bcl-2-associated athanogene-3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. [ncbi.nlm.nih.gov]

  It is described as a neuropathy since the problem originates in the nerves and not in the muscle tissue itself, which would be a myopathy. [uihc.org]

  Muscle Diseases Diseases of muscle are often classified as either muscular dystrophy or myopathy. [med.nyu.edu]

  [PubMed] [Free Full Text] Lessell S, Kuwabara T, Feldman RG: Myopathy and succinylcholine sensitivity. Am J Ophthalmol 1969, 68:789-96. [PubMed] Martyn JA, Richtsfeld M. [apicareonline.com]

  The lower motor neuron-type weakness may mimic a distal myopathy; however, electrophysiology is useful in differentiating between the two. [doi.org]

• Neuropathic Arthropathy

  Synonym(s): Charcot fever Charcot joint - a neuropathic arthropathy that occurs with tabes dorsalis (tabetic neurosyphilis). [medical-dictionary.thefreedictionary.com]

  Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. [ncbi.nlm.nih.gov]

• Foot Drop

  Abstract Gait abnormalities reported in childhood Charcot-Marie-Tooth disease (CMT) include foot-drop, reduced ankle power at push-off and increased knee and hip flexion for swing clearance ('steppage-gait'). [ncbi.nlm.nih.gov]

  They may include: Foot deformity (very high arch to feet) Foot drop (inability to hold foot horizontal) Loss of lower leg muscle, which leads to skinny calves Numbness in the foot or leg "Slapping" gait (feet hit the floor hard when walking) Weakness [nlm.nih.gov]

  The person may develop deformities of the feet such as high arches and hammertoes, and may experience foot drop (a difficulty in holding up the foot when the leg is lifted). Foot drop can cause changes in gait and frequent tripping. [villagepodiatrycenters.com]

  "Foot drop," caused by weakness in the feet and ankles. People with foot drop may have trouble lifting the foot at the ankle, so that toes point downward during walking. Foot drop causes a person to trip frequently and develop an abnormal gait. [ucsfbenioffchildrens.org]

• Steppage Gait

  The clinical similarities between CMT and FRDA include a symmetrical neuropathy (axonal in FRDA), steppage gait, and eventually scoliosis. [ncbi.nlm.nih.gov]

  This results in an abnormal "steppage" gait. People with a steppage gait tend to lift the affected leg higher as it swings through in order to allow the foot to clear the floor. Trips and falls become more frequent. [orthoinfo.aaos.org]

  Proprioceptive sensory loss can cause sensory ataxia and a steppage gait. Tasks involving fine motor control of the hands may also become progressively more difficult. [patient.info]

• Abnormal Gait

  Several distinct and abnormal gait patterns were identified in children with CMT, with increasing gait abnormalities in more functionally severe cases. [ncbi.nlm.nih.gov]

  Foot drop causes frequent tripping, and with increasing weakness and attempts at compensation, the affected person develops an abnormal gait. [mda.org]

  Foot drop causes a person to trip frequently and develop an abnormal gait. Loss of hand function. Contractures, a tightening of the joints that may cause deformities of the feet and hands. [ucsfbenioffchildrens.org]

  The average AI for our cohort was 1.8 (SD 1.4), indicating a mildly abnormal gait but with the ability to walk 25 feet in r 0.8, P 0.01), as evaluated on a questionnaire prior to enrolment in the study. [brain.oxfordjournals.org]

• Paresthesia

  Sensory loss in distal limbs, sometimes combined with painful sensory paresthesias may also develop. [doi.org]

  […] atrophy rather than foot involvement and absent sensory deficits in the early stages of the illness should raise a suspicion of carpal tunnel syndrome, neurogenic thoracic outlet syndrome, or multifocal motor neuropathy: In the absence of family history, paresthesia [ncbi.nlm.nih.gov]

• Hyporeflexia

  Common clinical manifestations of CMTX1 disease, as in other forms of Charcot-Marie-Tooth (CMT) disease, are distal muscle wasting and weakness, hyporeflexia, distal sensory disturbance, and foot deformities. [ncbi.nlm.nih.gov]

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.

• MRI Shows Cerebellar Atrophy

  In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy [ncbi.nlm.nih.gov]

• Hypoketotic Hypoglycemia

  hypoglycemia, and later-onset axonal sensory neuropathy with episodic myoglobinuria. [ncbi.nlm.nih.gov]

• Slow Nerve Conduction Velocities

  HMSN1 is the most common form of hereditary neuropathy, characterized by severely and uniformly slowed nerve conduction velocities and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes. [medlink.com]

  The EMG and NCV were consistent with demyelination and slow nerve conduction velocities. [podiatrytoday.com]

  Electrophysiological studies distinguish two major types – the demyelinating form, which is characterized by symmetrically slowed nerve conduction velocity (NCV; usually 1 If this pattern is recognized, certain genes are more likely to be involved than [doi.org]

  Little new was added to this description until the late 1950s, when Gilliatt and Thomas noted that some patients with CMT had slow nerve conduction velocities (NCVs) ( Gilliatt and Thomas, 1957 ). [brain.oxfordjournals.org]

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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