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44-548: Charcot–Marie–Tooth disease ( CMT ) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder , affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and

88-449: A deficient amount of glycyl-tRNA in cells, preventing the elongation phase of protein synthesis . Elongation is a key step in protein production, so when there is a deficiency of glycyl-tRNA, protein synthesis is unable to continue at glycine sites. GARS1 mutations also stall initiation of translation due to a stress response that is induced by glycine addition failure. By stalling elongation and initiation of translation, CMT2D mutations in

132-533: A definitive diagnosis, but not all the genetic markers for CMT are known. CMT is first most noticed when someone develops lower leg weakness, such as foot drop, or foot deformities, including hammertoes and high arches, but signs alone do not lead to diagnosis. Patients must be referred to a physician specialising in neurology or rehabilitation medicine. To see signs of muscle weakness, the neurologist may ask patients to walk on their heels or to move part of their leg against an opposing force. To identify sensory loss,

176-513: A physical evaluation that looks for muscle atrophy, weakness, and sensory responses. In addition to this, electromyography and motor nerve conduction tests can help clinicians decide what type of motor and sensory neuropathy it is and how severe the disease is. Final confirmation can come through genetic testing . Charcot–Marie–Tooth disease was first described in 1886 by Jean-Martin Charcot , Pierre Marie , and independently Howard Henry Tooth . In

220-554: A result of severe muscular weakness and atrophy. In patients with demyelinating neuropathy, symptoms are due to slow nerve conduction velocities; however people with axonal degradation have average-to-normal nerve conduction velocities. All hereditary motor and sensory neuropathies are inherited. Chromosomes 17 and 1 seem to be the most common chromosomes with mutations. The disease can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. Patients with hereditary motor and sensory neuropathies are diagnosed through

264-442: A secondary injury, as prolonged periods of limited mobility can drastically accelerate symptoms of CMT. Pain due to postural changes, skeletal deformations, muscle fatigue, and cramping is fairly common in people with CMT. It can be mitigated or treated by physical therapies, surgeries, and corrective or assistive devices. Analgesic medications may also be needed if other therapies do not provide relief from pain. Neuropathic pain

308-443: A similarly nonspecific finding that indicates a cycle of denervation / reinnervation . Normally, type I and type II muscle fibers show a checkerboard-like random distribution. However, when reinnervation occurs, the group of fibers associated with one nerve are of the same type. The standard for indicating fiber type is histoenzymatic adenosine triphosphatase (ATPase at pH 9.4). Often, the most important goal for patients with CMT

352-663: Is also present in oligodendrocytes , demyelination can appear in the CNS as well. Schwann cells create the myelin sheath by wrapping their plasma membranes around the axon. These Schwann cells work together with neurons and fibroblasts to create a functional nerve. Schwann cells and neurons exchange molecular signals by way of gap junctions that regulate survival and differentiation Demyelinating Schwann cells cause abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction. The myelin sheath allows nerve cells to conduct signals faster. When

396-521: Is considered to be targetable for CMT2D treatment. CMT can also be produced by X-linked mutations, in which case it is called X-linked CMT (CMTX). In CMTX, mutated connexons create nonfunctional gap junctions that interrupt molecular exchange and signal transport. The mutation can appear in the GJB1 gene coding for the connexin 32 protein, a gap junction protein expressed in Schwann cells. Because this protein

440-597: Is integral to protein translation and attaches glycine to its cognate tRNA. Many different mutations have been found in CMT2D patients, and it remains unclear how mutations in GARS1 cause CMT2D. However, it is thought that mutant glycyl-tRNA synthetase (GlyRS) interferes with transmembrane receptors, causing motor disease, and that mutations in the gene could disrupt the ability of GlyRS to interact with its cognate RNA, disrupting protein production. The GARS1 mutations present in CMT2D cause

484-496: Is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925). Ankyrin : Long QT syndrome 4 Hereditary motor and sensory neuropathies The term "hereditary motor and sensory neuropathy" was used mostly historically to denote the more common forms Charcot–Marie–Tooth disease (CMT). With

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528-553: Is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity vary from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies , as well as postherpetic neuralgia and complex regional pain syndrome , among other diseases. Atypical presentations of CMT can also lead to leg muscles, specifically

572-526: Is one of the 23 pairs of chromosomes in humans . People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA ) and represents between 2.5 and 3% of the total DNA in cells . Chromosome 17 contains the Homeobox B gene cluster. The following are some of the gene count estimates of human chromosome 17. Because researchers use different approaches to genome annotation their predictions of

616-424: Is thought to be caused by aberrant gain-of-function missense mutations . The GARS1 gene is a protein-coding gene responsible for the encoding of glycyl-tRNA synthetase (GlyRS). Glycyl-tRNA synthetase is a class II aminoacyl-tRNA synthetase and acts as the catalyst for the synthesis of glycyl-tRNA by covalently bonding amino acids with their corresponding cognate tRNAs for protein translation . Glycyl-tRNA synthetase

660-406: Is to maintain movement, muscle strength, and flexibility. Therefore, an interprofessional team approach with occupational therapy (OT), physical therapy (PT), orthotist, podiatrist, and or orthopedic surgeon is recommended. Appropriate footwear is also very important for people with CMT, but they often have difficulty finding well-fitting shoes because of their high-arched feet and hammertoes. Due to

704-481: The neuromuscular junction (NMJ). The neuromuscular junction is abnormal in CMT2D mice, with subjects showing neuromuscular junction degeneration in hind muscles. The dorsal root ganglia (DRG) are also affected via aberrant sensory neuron fate, meaning that sensory neuron cell fates are abnormally determined. CMT2D mice have fewer proprioceptive and mechanosensitive neurons, but have more nociceptive neurons, possibly due to mutant GlyRS aberrantly interacting with

748-400: The number of genes on each chromosome varies (for technical details, see gene prediction ). The most conservative estimate, from CCDS , represents a lower bound on the total number of human protein-coding genes. The following is a partial list of genes on human chromosome 17. For complete list, see the link in the infobox on the right. Groups of similar genes: The following are some of

792-434: The soleus muscle , forms the triceps surae muscles (distal calf muscles), occurs causing the known "stork leg deformity". In most cases, ankle-foot orthoses that have functional elements for the foot lifting and adjustable control of the lowering of the forefoot make sense. Weak calf muscles lead to insufficient activation of the forefoot lever. This leads to an additional increasing uncertainty when standing and walking. If

836-464: The 1950s, further classification occurred and separated patients into two distinct groups. Group one was characterized by slow nerve conduction velocities and demyelinating neuropathy. Group two was characterized by mostly normal nerve conduction velocities and degeneration of axons. In 1968, HMSN were classified again into seven groups: Database There is currently no known pharmacological treatment to hereditary motor and sensory neuropathy. However,

880-404: The Briton Howard Henry Tooth (1856–1925). There is no known cure. Care focuses on maintaining function. CMT was previously classified as a subtype of muscular dystrophy . Symptoms of CMT usually begin in early childhood or early adulthood but can begin later. Some people do not experience symptoms until their early 30s or 40s. Usually, the initial symptom is foot drop or high arches early in

924-585: The GARS1 gene cause translational repression, meaning that overall translation is inhibited. GARS1-associated axonal neuropathy is progressive , meaning that it worsens over time. Unknown mechanisms are thought to cause the chronic neurodegeneration resulting from the aberrant GlyRS; however, one theory on the mechanism for the disease is VEGF deficiency. Mutant GlysRS interferes with neuronal transmembrane receptors, including neuropilin 1 (Nrp1) and vascular endothelial growth factor (VEGF) , causing neuropathy. GARS-CMT2D mutations alter GlyRS and allow it to bind to

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968-500: The Nrp1 receptor, interfering with the normal binding of Nrp1 to VEGF. While enhanced expression of VEGF improves motor function, reduced expression of Nrp1 worsens CMT2D; because Nrp1 binds to mutant GlyRS in mutant GARS1-CMT2D individuals, Nrp1 expression is reduced, in turn worsening motor function. Mice with deficient VEGF demonstrate motor neuron disease over time. Thus, the VEGF/Nrp1 pathway

1012-404: The axon towards the synapses . This prevents the synapses from functioning. CMT is a heterogeneous disease and the mutations linked to it may occur in many different genes. Based on the affected gene, CMT is categorized into several types and subtypes. CMT2 variants are typically referred to as axonal neuropathies due to the axonal degeneration observed. CMT2 variants are a result of damage to

1056-412: The axon. Chromosome 17 The most common cause of CMT (70–80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22 . Chromosome 1 Some mutations affect the gene MFN2 , on chromosome 1 , which codes for a mitochondrial protein. Mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down

1100-478: The calf muscles are weak, an orthosis should therefore be equipped with functional elements to activate the forefoot lever. An orthotic joint with an adjustable dynamic dorsiflexion stop with a strong spring in combination with a lower leg shell in front of the shin is recommended for this. Such orthoses help to control foot drop, and instability of the foot and ankle and offer the patient a better sense of balance when standing and walking without restricting mobility and

1144-479: The calves, enlarging. This hypertrophic type of CMT is not caused by the muscles enlarging directly, but by pseudohypertrophy of the legs as fatty tissue enters the leg muscles. Charcot–Marie–Tooth disease is caused by genetic mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect

1188-424: The course of the disease. This can be accompanied by hammertoe , where the toes are always curled. Wasting atrophy of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses. High-arched feet ( pes cavus ) or flat-arched feet ( pes planus ) are classically associated with

1232-576: The degradation of sensory axons) are observed along with motor deficits; otherwise, distal hereditary motor neuropathy type V is diagnosed. It is unknown why sensory involvement is so varied between GARS1 neuropathy patients. Symptoms of CMT2D include foot deformity, muscle weakness and cramping, compromised reflexes, loss of sensation, and muscle atrophy, and are similar to the symptoms of both CMT1 and CMT2 variants. Symptoms and severity vary from patient to patient. Mice are often used to model CMT2D, and typically demonstrate aberrant neuromuscular function at

1276-656: The disease can vary. Involuntary grinding of teeth and squinting are prevalent and often go unnoticed by the person affected. Breathing can be affected in some, as can hearing, vision, and neck and shoulder muscles. Scoliosis is common, causing hunching and loss of height. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords ). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as severe emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from

1320-561: The disease. Most forms of HMSN affect males earlier and more severely than females, but others show no predilection to either sex. HMSN affects all ethnic groups, with the most common forms having no racial predilection, but other recessively inherited forms tending to impact specific ethnic groups. Onset of HMSN is most common in early childhood, with clinical effects occurring before the age of 10, but some symptoms are lifelong and progress slowly. Therefore, these symptoms do not appear until later in life. Chromosome 17 Chromosome 17

1364-481: The disease. The mother and father each had one normal and one mutant copy of this gene and had mild or no symptoms. The offspring who inherited two mutant genes presented fully with the disease. The constant cycle of demyelination and remyelination , which occurs in CMT, can lead to the formation of layers of myelin around some nerves, termed an "onion bulb". These are also seen in chronic inflammatory demyelinating polyneuropathy . Muscles show fiber type grouping,

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1408-554: The disorder. Loss of touch sensation in the feet, ankles, and legs as well as in the hands, wrists, and arms occurs with various types of the disease. Early- and late-onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. Sensory and proprioceptive nerves in the hands and feet are often damaged, while unmyelinated pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping. Symptoms and progression of

1452-404: The dynamics of the ankle joint. Studies confirm the positive effect of orthoses with adjustable functional elements in patients with paralysis of these muscle groups. It is of great advantage if the resistances of the two functional elements can be set separately from one another in the two directions of movement, dorsiflexion and plantar flexion . The severity of symptoms varies widely even for

1496-400: The extracellular region of tropomyosin receptor kinase, or Trk, receptors. Trk receptors are crucial to the survival and development of sensory neurons; when disrupted, nerve development and survival is disrupted as well, possibly leading to the abnormal sensory neuron counts observed in CMT2D mice. CMT2D is a result of autosomal dominant mutations in the human GARS1 gene located at 7p14.3 and

1540-512: The genetic cause of a particular patient's disease was precisely determined by sequencing the whole genome of an affected individual. This was done by the scientists employed by the Charcot Marie Tooth Association (CMTA). Two mutations were identified in a gene, SH3TC2 , known to cause CMT. Researchers then compared the affected patient's genome to the genomes of the patient's mother, father, and seven siblings with and without

1584-563: The identification of a wide number of genetically and phenotypically distinct forms of CMT, the term HMSN is now used less frequently. Neuropathy disorders usually have onset in childhood or young adulthood. Motor symptoms seem to be more predominant than sensory symptoms. Symptoms of these disorders include: fatigue, pain, lack of balance, lack of feeling, lack of reflexes, and lack of sight and hearing, which result from muscle atrophy. Patients can also have high arched feet, hammer toes, foot drop, foot deformities, and scoliosis. These symptoms are

1628-420: The lack of good sensory reception in the feet, CMT patients may also need to see a podiatrist for assistance in trimming nails or removing calluses that develop on the pads of the feet. Lastly, patients can also decide to have surgery performed by a podiatrist or an orthopedic surgeon. Surgery may help to stabilize the patients' feet or correct progressive problems. These procedures include straightening and pinning

1672-574: The majority of people with these diseases are able to walk and be self-sufficient. Some methods of relief for the disease include physical therapy, stretching, braces, and sometimes orthopedic surgery. Since foot disorders are common with neuropathy, precautions must be taken to strengthen these muscles and use preventative care and physical therapy to prevent injury and deformities. Hereditary motor and sensory neuropathy are relatively common and are often inherited with other neuromuscular conditions, and these comorbidities cause an accelerated progression of

1716-421: The myelin sheath is damaged, however, nerve signals are slower. This can be measured by a common neurological test, electromyography . When the axon is damaged, the result is a reduced compound muscle action potential . CMT can be diagnosed through three different forms of tests: measurement of the speed of nerve impulses ( nerve conduction studies ), a biopsy of the nerve, and DNA testing. DNA testing can give

1760-444: The nerve axons , rather than damage to the myelin sheath (as is the case with CMT1). Damaged axons cause slowed transmission of signals to the muscles and brain, causing symptoms including muscle atrophy, weakness, decreased sensitivity, and foot deformity. Symptoms of CMT2 variants typically appear between the ages of 5 and 25. CMT2D is one of 31 CMT2 variants, and is only diagnosed if sensory deficits (such as loss of sensation due to

1804-406: The neurologist tests for deep-tendon reflexes, such as the knee jerk, which are reduced or absent in CMT. The doctor may also ask about the patient's family history since CMT is hereditary. The lack of family history does not rule out CMT but is helpful to rule out other causes of neuropathy, such as diabetes or exposure to certain chemicals or drugs. In 2010, CMT was one of the first diseases where

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1848-445: The physical condition of the affected individuals. If the muscles of the lower extremities are weak, it makes sense to prescribe custom-fabricated orthotics . Depending on which muscle groups are affected, the correct orthoses with appropriate functional elements should be prescribed. A weakness of the tibialis anterior muscle , which lifts the feet, is usually accompanied by an atrophy of the gastrocnemius muscle which, together with

1892-403: The same type of CMT. Cases of monozygotic twins with varying levels of disease severity have been reported, showing that identical genotypes are associated with different levels of severity (see penetrance ). Some patients can live a normal life and are almost or entirely asymptomatic. A 2007 review stated that "life expectancy is not known to be altered in the majority of cases." The disease

1936-590: The toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability. CMT patients must take extra care to avoid falling as fractures take longer to heal in someone with an underlying disease process. Additionally, the resulting inactivity may cause the CMT to worsen. The Charcot–Marie–Tooth Association classifies the chemotherapy drug vincristine as a "definite high risk" and states, "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms." Several corrective surgical procedures can be done to improve

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