Genetic Disorders

Fesalbon , Mary gem 2NRS1

CharcotMarie Tooth disease

CharcotMarieTooth disease
CharcotMarieTooth disease (CMT), also known as Morbus Charcot-Marie-Tooth, CharcotMarie-Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN), hereditary sensorimotor neuropathy (HSMN), or peroneal muscular atrophy, is an inherited demyelinating disease of the peripheral nervous system. CMT is predominantly characterized by progressive loss of muscle tissue and touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms in 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. High arched feet (pes cavus) are classically associated with the disorder. Sensory and proprioceptive nerves in the hands and feet are often damaged, while pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 23,000 people in the UK and 125,000 people in the USA. It was previously considered a type of muscular dystrophy

What genes are related to Charcot-Marie-Tooth disease?

Charcot-Marie-Tooth disease can be caused by changes in many different genes that are essential to the function of peripheral nerves in the feet, legs, and hands. These changes impair axons that transmit nerve impulses or affect the specialized cells that produce myelin. As a result of these disrupted functions, nerve cells slowly lose the ability to stimulate the muscles and to transmit sensory signals. Charcot-Marie-Tooth disease is usually categorized by the specific gene that is altered. The list of these genes continues to grow as researchers identify additional mutations associated with the various types of the disorder. Type 1 is caused by mutations in the following genes: PMP22 (subtypes 1A and 1E), MPZ(subtype 1B), LITAF (subtype 1C), EGR2 (subtype 1D), and NEFL (subtype 1F). Type 2 Charcot-Marie-Tooth disease results from alterations in the following genes: MFN2 and, rarely,KIF1B (subtype 2A), RAB7A (subtype 2B), LMNA (subtype 2B1), TRPV4 (subtype 2C), BSCL2 andGARS (subtype 2D), NEFL (subtype 2E), HSPB1 (subtype 2F), MPZ (subtypes 2I and 2J), GDAP1(subtype 2K), and HSPB8 (subtype 2L). Certain DNM2 gene mutations also cause a form of type 2 Charcot-Marie-Tooth disease.

Type 4 Charcot-Marie Tooth disease is caused by mutations in the following genes: GDAP1 (subtype 4A), MTMR2 (subtype 4B1), SBF2 (subtype 4B2), SH3TC2 (subtype 4C), NDRG1 (subtype 4D),EGR2 (subtype 4E), PRX (subtype 4F), FGD4 (subtype 4H), and FIG4 (subtype 4J). Intermediate forms of the disorder are caused by an altered DNM2 or YARS gene. Type X Charcot-Marie-Tooth disease is caused by mutations in the GJB1 (subtype X1) and PRPS1 (subtype X5) genes. Mutations in additional genes that have not been identified also cause Type X (subtypes X2, X3, and X4) and intermediate forms of Charcot-Marie-Tooth disease.

How do people inherit CharcotMarie-Tooth disease?

The pattern of inheritance varies with the type of Charcot-Marie-Tooth disease. Type 1, most cases of Type 2, and intermediate forms of Charcot-Marie-Tooth disease are inherited in an autosomal dominant pattern. This pattern of inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one affected parent. Type 4 Charcot-Marie-Tooth disease and a few forms of Type 2 are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Type X is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. The inheritance is dominant if one copy of the altered gene is sufficient to cause the condition. In most cases, affected males, who have the alteration on their only copy of the X chromosome, experience more severe symptoms of the disorder than females, who have two X chromosomes. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. All daughters of affected men will have one altered X chromosome, but may only have mild symptoms of the disorder. Some cases of Charcot-Marie-Tooth disease result from a new mutation and occur in people with no history of the disorder in their family.

Signs and symptoms

Symptoms of CMT usually begin in late childhood or early adulthood. Some people do not experience symptoms until their early thirties or forties. Usually, the initial symptom is foot drop early in the course of the disease. This can also cause claw toe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted bottle" appearance. Weakness in the hands and forearms occurs in many people later in life as the disease progresses. Symptoms and progression of the disease can vary. Breathing can be affected in some; so can hearing, vision, as well as the neck and shoulder muscles. Scoliosis is common. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can chewing, swallowing, and speaking (as vocal cords atrophy). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as extreme emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury as prolonged periods of limited mobility can drastically accelerate symptoms of CMT. Neuropathic pain is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity varies 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 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.

Causes
CharcotMarieTooth disease is caused by 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 the axon. The most common cause of CMT (70-80% of the cases) is the duplication of a large region in chromosome 17p12 that includes the gene PMP22. Some mutations affect the gene MFN2, which codes for a mitochondrial protein. Cells contain separate sets of genes in their nucleus and in their mitochondria. In nerve cells, the mitochondria travel down the long axons. In some forms of CMT, mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the synapses. This prevents the synapses from functioning. CMT is divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with frequent overlap. Another cell Involved in CMT is the Schwann cell, which creates the myelin sheath, by wrapping its plasma membrane around the axon in a structure that is sometimes compared to a Swiss roll Neurons, Schwann cells, and fibroblasts work together to create a working nerve. Schwann cells and neurons exchange molecular signals that regulate survival and differentiation. These signals are disrupted in CMT.

 Demyelinating Schwann cells causes 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 the myelin sheath is damaged, nerve signals are slower, and this can be measured by a common neurological test ,electromyography. When the axon is damaged, on the other hand, this results in a reduced compound muscle action potential (CMAP).

Diagnosis
CMT can be diagnosed through symptoms, through measurement of the speed of nerve impulses (electromyography), through biopsy of the nerve, and through DNA testing. DNA testing can give a definitive diagnosis, but not all the genetic markers for CMT are known.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 or a physical medicine and rehabilitation physician (physiatrist). To see signs of muscle weakness the neurologist will ask patients to walk on their heels or to move part of their leg against an opposing force. In order to identify sensory loss the neurologist will test for deep tendon reflexes, such as the knee jerk, which are reduced or absent in CMT. The doctor will also ask about family history because CMT is hereditary. The lack of family history does not rule out CMT, but it will allow the doctor 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 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) [9][10] 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 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 that inherited two mutant genes presented fully with the disease. Sequencing the initial patient's whole genome cost $50,000, but researchers estimated that it would soon cost $5,000 and become common.

Management
Although there is no current standard treatment, the use of ascorbic acid has been proposed, and has shown some benefit in animal models. A clinical trial to determine the effectiveness of high doses of ascorbic acid (vitamin C) in treating humans with CMT type 1A has been conducted. The results of the trial upon children have shown that a high dosage intake of ascorbic acid is safe but the efficacy endpoints expected were not met.In 2010, a study published in the Journal Science indicated that scientists had identified those proteins that control the thickness of myelin sheath. This discovery is expected to open the avenue to new treatments in the coming years. The Charcot-Marie-Tooth Association classifies the chemotherapy drug vincristine as a "definite high risk" and states that "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms." There are also several corrective surgical procedures that can be done to improve physical condition.

The most important activity for patients with CMT is to maintain what movement, muscle strength and flexibility they have. Therefore, physical therapy and moderate activity are recommended but overexertion should be avoided. A physiotherapist should be involved in designing a exercise program that fits a patients personal strengths and flexibility. Bracing can also be used to correct problems caused by CMT. Gait abnormalities can be corrected by the use of either articulated (hinged) or unarticulated, braces called AFOs (ankle-foot orthoses). These braces help control foot drop and ankle instability and often provide a better sense of balance for patients. 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 hammer toes. Due to the lack of good sensory reception in the feet, CMT patients may also need to see a podiatrist for help in trimming nails or removing calluses that develop on the pads of the feet. A final decision a patient can make is to have surgery. Using a podiatrist or an orthopedic surgeon, patients can choose to stabilize their feet or correct progressive problems. These procedures include straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability. CMT patients must take extra care to avoid falling because 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 that "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms." There are also several corrective surgical procedures that can be done to improve physical condition.