What is Charcot-Marie-Tooth?
Charcot-Marie-Tooth (CMT) is a group of genetically inherited diseases that result in nerve damage to peripheral nerves in the legs and arms resulting in an inability to properly use the muscles in these areas. Usually appearing in adolescence or early adulthood, someone with CMT may have smaller and weaker muscles of the arms and legs, loss of sensation, and difficulty walking. CMT is progressive as it slowly causes the onset of these symptoms over time, however, while incurable, it is usually non-fatal.
PMP22 Function in Charcot-Marie-Tooth
Peripheral Myelin Protein 22 (PMP22) is a gene that gives instructions to produce a protein with the same name, PMP22. This protein is produced by Schwann cells which are responsible for creating myelin, a covering of the nerves, that helps in sending signals to and from the brain as well as protecting the nerve. In CMT1A the most common form of CMT, the PMP22 gene is contained in a 1.4-Mb duplication on chromosome 17pl11.2 [5].
This excess protein interferes with Schwann cell processes including the creation of myelin. This results in the destruction and loss of myelin (demyelination). Myelin is necessary for the proper sending of signals from the brain and as a result of demyelination, peripheral nerves can no longer activate muscles or properly send information back to the brain, giving way to muscle weakness and loss of sensation as primary symptoms. [2]
Prevalence and Inheritance
CMT1A is an autosomal dominant disorder, meaning that it can be passed on even if only one copy of the responsible mutated PMP22 gene is given by the parent. Because it is autosomal dominant, an effected parent that has children has a 50% chance of passing the mutated PMP22 gene, and therefore CMT1A onto the child. CMT1A can also occur through de novo mutations in the PMP22 gene, meaning that neither parent had the mutated gene, however the PMP22 gene spontaneously mutated in the child resulting in the disorder [1]. CMT is the most common genetically inherited disorder that involves the peripheral nerves, and it effects an estimated 1 in 3,300 people [3]. CMT1A is a subtype of CMT caused by the duplication of PMP22, and is the most common. However different subtypes including CMT1B, CMT2A, CMT4A, etc., exist and are caused by different genetic mutations [3].
Signs and Symptoms
Early symptoms of CMT1A usually occur in childhood. These symptoms include problems running dur to high arches, hammertoes, and weakened ankles requiring braces. Symptoms involving the weakening of hand muscles usually occur around 10 years after foot problems. In addition to weakening of the muscles of the hands and feet, decreased sense of touch, heat and pain is also typical. The most common symptoms in CMT1A patients include decreased motor and sensory nerve conduction velocity, muscle weakness, sensory impairment and hyporeflexia or decreased reflex response [1]. Despite this, most patients remain able to walk and live a normal life expectancy. Tests to determine CMT1A include nerve conduction studies to test how well the patients nerves conduct a signal and genetic testing to see if gene duplication of PMP22 has occurred [4]. |
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Gaps in Knowledge
Some of the future research questions regarding CMT1A include
- The exact function of PMP22 in causing CMT1A
- How can controlling gene dosage of PMP22 impact CMT1A symptoms?
- How can we control the gene dosage of PMP22?
- How can we prevent demyelination of the nerve through supportive medicine?
Other Resources
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
References
[1] Charcot-Marie-Tooth disease type 1a. (n.d.). Retrieved February 23, 2021, from https://rarediseases.info.nih.gov/diseases/1245/charcot-marie-tooth-disease-type-1a
[2] PMP22 gene: MedlinePlus Genetics. (2020, August 18). Retrieved February 23, 2021, from https://medlineplus.gov/genetics/gene/pmp22
[3] Charcot-Marie-Tooth disease: MedlinePlus Genetics. (2020, September 08). Retrieved February 23, 2021, from https://medlineplus.gov/genetics/condition/charcot-marie-tooth-disease/
[4] Genetic testing. (2019, April 22). Retrieved February 23, 2021, from https://www.cmtausa.org/living-with-cmt/find-help/genetic-testing/
[5] Patzkó, A., & Shy, M. E. (2011). Update on Charcot-Marie-Tooth disease. Current neurology and neuroscience reports, 11(1), 78–88. https://doi.org/10.1007/s11910-010-0158-7
[2] PMP22 gene: MedlinePlus Genetics. (2020, August 18). Retrieved February 23, 2021, from https://medlineplus.gov/genetics/gene/pmp22
[3] Charcot-Marie-Tooth disease: MedlinePlus Genetics. (2020, September 08). Retrieved February 23, 2021, from https://medlineplus.gov/genetics/condition/charcot-marie-tooth-disease/
[4] Genetic testing. (2019, April 22). Retrieved February 23, 2021, from https://www.cmtausa.org/living-with-cmt/find-help/genetic-testing/
[5] Patzkó, A., & Shy, M. E. (2011). Update on Charcot-Marie-Tooth disease. Current neurology and neuroscience reports, 11(1), 78–88. https://doi.org/10.1007/s11910-010-0158-7
Video References
[1] College of Podiatry. (Feb 28, 2019). Charcot-Marie-Tooth disease (CMT) & Podiatry [Video] https://www.youtube.com/watch?v=fa6ZKLWquuI&feature=emb_title