Charcot–Marie–Tooth disease
Charcot–Marie–Tooth disease | |
---|---|
Other names | Charcot–Marie–Tooth neuropathy, peroneal muscular atrophy, Dejerine-Sottas syndrome |
electromyogram (EMG) | |
Differential diagnosis | Muscular dystrophy |
Treatment | Management to maintain function |
Prognosis | Progressive |
Frequency | Prevalence: 1 in 2,500[1][2] |
Charcot–Marie–Tooth disease (CMT) is a
There is no known cure. Care focuses on maintaining function. CMT was previously classified as a subtype of muscular dystrophy.[3]
Signs and symptoms
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
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. High-arched feet (
Symptoms and progression of 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,[10][11] as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords).[12] 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 a secondary injury, as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.[13]
Causes
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 the axon.[16]
Classification
CMT is a
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 1
Some mutations affect the gene
X-linked CMT and Schwann cells
CMT can also be produced by X-linked mutations and is named X-linked CMT (CMTX). In CMTX, mutated connexons create nonfunctional gap junctions that interrupt molecular exchange and signal transport.[21][22][23]
The mutation can appear in the
Schwann cells create the myelin sheath, by wrapping its plasma membrane around the axon.[21]
Neurons, Schwann cells, and fibroblasts work together to create a functional nerve. Schwann cells and neurons exchange molecular signals by gap junctions that regulate survival and differentiation.[citation needed]
Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.[3]
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, though, this results in a reduced compound muscle action potential.[25]
GARS1-Related Axonal Neuropathy
CMT2 types are typically referred to as axonal neuropathies due to the axonal degeneration observed. CMT2 types are a result of damage to 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 types typically appear between the ages of 5 and 25.[26] CMT2D is one of 31 Charcot–Marie–Tooth type 2 forms 1 and is only diagnosed if sensory deficits (such as loss of sensation due to 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.[27] 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 other both CMT1 and CMT2 types. Symptoms and severity vary from patient to patient.[28]
Mice are often used to model CMT2D and typically demonstrate aberrant neuromuscular function at the neuromuscular junction (NMJ).[29][30][31] The neuromuscular junction is abnormal in CMT2D mice, with subjects showing neuromuscular junction degeneration in hind muscles. The dorsal root ganglia (DRG) is 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 the extracellular region of tropomyosin receptor kinase, or Trk, receptors.[32] 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.[27]
CMT2D is a result of autosomal dominant mutations in the human GARS1 gene located at 7p14.3 [33] and is thought to be caused by aberrant gain-of-function missense mutations.[27] 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 is integral to protein translation and attaches glycine to its cognate tRNA.[34]
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[35][36] 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 a deficient amount of glycyl-tRNA in cells, preventing the elongation phase of protein synthesis. Because elongation is a key step in protein production, ribosomes are unable to continue protein synthesis at glycine sites. GARS1 mutations also stall initiation of translation. Glycine addition failure causes a stress response that further stalls protein production, preventing initiation of translation. By stalling elongation and initiation of translation, CMT2D mutations in the GARS1 gene cause translational repression, meaning that overall translation is inhibited.[37]
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 for disease is VEGF-deficiency. Mutant GlysRS interferes with neuronal transmembrane receptors, including neuropilin 1 (Nrp1) and vascular endothelial growth factor (VEGF), causing neuropathy.[36] GARS-CMT2D mutations alter GlyRS and allow it to bind to 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 is considered to be targetable for CMT2D treatment.[26]
Diagnosis
CMT can be diagnosed through three different forms of tests: measurement of the speed of nerve impulses (
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).[39][18] 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 who inherited two mutant genes presented fully with the disease.[18]
Histology
The constant cycle of
Management
Often, the most important goal for patients with CMT 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.[8] PT typically focuses on muscle-strength training, muscle stretching, and aerobic exercise, while OT can provide education on energy conservation strategies and activities of daily living. Physical therapy should be involved in designing an exercise program that fits a person's personal strengths and flexibility. Bracing can also be used to correct problems caused by CMT. An orthotist may address gait abnormalities by prescribing the use of orthotics.[citation needed]
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 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 the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability.[13] 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.[13] 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."[42] Several corrective surgical procedures can be done to improve the physical condition of the affected individuals.[43]
Orthotics
If the muscles of the lower extremities are weak, it makes sense to prescribe custom-fabricated
Prognosis
The severity of symptoms varies widely even for 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 are able to live a normal life and are almost or entirely asymptomatic.[50] A 2007 review stated that, "life expectancy is not known to be altered in the majority of cases."[51]
History
The disease is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940),[5] and the Briton Howard Henry Tooth (1856–1925).[6]
See also
- Charcot–Marie–Tooth disease classifications
- Palmoplantar keratoderma and spastic paraplegia
- Hereditary motor and sensory neuropathies
- Hereditary motor neuropathies
- Low copy repeats
- Christina's World
References
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- ^ a b Charcot JM (1886). "Sur une forme particulière d'atrophie musculaire progressive, souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains" [On a particular form of progressive muscular atrophy, often familial, beginning with the feet and legs and later reaching the hands]. Revue Médicale (in French). 6: 97–138.
- ^ a b Tooth HH (1886). The peroneal type of progressive muscular atrophy (MD thesis). London.
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- ^ a b c "Charcot-Marie-Tooth Disease Fact Sheet". National Institute of Neurological Disorders and Stroke. Retrieved 2022-04-23.
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Typically autosomal dominant inheritance pattern associated with scoliosis and foot deformities (high or flat arches).
- ^ "CMT News". Lindacrabtree.com. Archived from the original on 2016-08-05. Retrieved 2016-11-13.
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- ^ "Charcot-Marie-Tooth Disease Fact Sheet". National Institute of Neurological Disorders and Stroke. 2016-01-14. Archived from the original on 2016-11-19. Retrieved 2016-11-13.
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- ^ "OMIM Entry- * 600287 - Glycl-tRNA Synthetase 1; GARS1". Online Mendelian Inheritance in Man. Retrieved 2022-05-10.
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- ^ Wade N (2010-03-10). "Disease Cause Is Pinpointed With Genome". New York Times. Archived from the original on 2022-01-01.
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- ^ "Medical Alert". Charcot-Marie-Tooth Association. Archived from the original on 2007-07-02. Retrieved 2007-08-21.
- Levine, DB, Burke S, Bansal M. Neuropathic spinal atrophy in Charcot–Marie–Tooth disease. J Bone Joint Surg. 1997; 79-A:1235–39.
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External links
- Media related to Charcot-Marie-Tooth disease at Wikimedia Commons
- Charcot–Marie–Tooth disease at Curlie