BPG BLOG (34)

Rare Disease Highlight: Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth Disease (CMT) is a group of genetic disorders characterized by progressive damage to motor and/or sensory nerves (Morena et al., 2019; NIH, 2018; NORD, 2021). CMT occurs due to mutations in certain genes responsible for producing proteins involved in the structure and function of peripheral nerve axons, nerve fibers that carry nerve impulses between cells, and the myelin sheath, a protective layer that covers axons (NIH, 2018). Scientists have discovered over 100 genes responsible for various forms of CMT (NORD, 2021). However, a single gene, known as PMP22, when duplicated, is responsible for over 50% of all reported CMT cases (Morena et al., 2019; NORD, 2021). All 100 identified genes in CMT can be passed down from parents to children in an autosomal dominant, autosomal recessive, X-linked, or X-linked dominant manner. Autosomal refers to genes located on non-sex chromosomes, while X-linked are directly located in the sex chromosome known as X-chromosome. Biologically, females have two X chromosomes while males only have one. Each chromosome has two working copies of a gene, inherited from each parent. In dominant genetic diseases, only one mutated copy of the gene is needed to induce the disease. However, in recessive genetic diseases, both mutated copies of the gene are required for the disease to be apparent (NORD, 2021). CMT is classified into several subtypes depending on the inheritance pattern and the physiological cause of the disease, which can be demyelinating (loss of the myelin sheath), axonal, or intermediate. It is possible to have two or more types of CMT based on the mutations of two or more genes (Morena et al., 2019; NIH, 2018; NORD, 2021). The two most common subtypes of CMT are CMT type 1 (CMT1) 1 and type 2 (CMT2). CMT1, inherited in an autosomal dominant manner, is a demyelinating form of CMT characterized by axonal loss and neuronal dysfunction and associated with PMP22 duplication. CMT2, also inherited in an autosomal dominant manner, is characterized by axonal degeneration, which results in the loss of communication between brain cells (known as neurons). Other less common types include CMT type 4 (CMT4), an autosomal recessive disorder, and CMT type X (CMTX), an X-linked dominant disease (Morena et al., 2019; NORD, 2021).

CMT affects people of all races and ethnic groups, and symptoms appear in adolescence, early childhood, or middle age (NORD, 2021). Despite the genetic variance of the disease, the clinical presentation of CMT patients is similar in all cases. CMT patients present with sensorimotor neuropathy. Neuropathy is defined as the damage or dysfunction of one or more nerves that typically results in numbness, tingling, muscle weakness, and pain in the affected area (Cleveland Clinic, 2019; Fledrich et al., 2012; Notterpek et al., 1999). Sensorimotor means the nerves involved in this neuropathy have both sensory and motor functions. Symptoms initially appear in the longest nerve fibers, mainly the distal legs (meaning the part of the leg located further from the torso or center of the body) followed by the hands, and they include decreased sensitivity to heat, muscle weakness, and balance problems. The disease is progressive in nature and can lead to impairments to fine motor skills, foot and leg deformities, scoliosis (a sideways curvature of the spine), and hip displacement (NIH, 2018; NORD, 2021).

There is no cure for CMT. The current standard of care focuses on treating specific symptoms and providing supportive care, including physical therapy, shoe orthotics (devices designed to support the feet), leg braces, and surgery to correct deformities (Morena et al., 2019; NORD, 2021). Patients live with disease-related disabilities which continue to progress despite available treatments, impacting their overall quality of life. The development of novel treatments that target the root cause of CMT are essential to address this unmet medical need and provide patients with curative options for their disease.

References

  • Cleveland Clinic. (2019). Neuropathy (Peripheral Neuropathy). Retrieved May 6, 2022 from https://my.clevelandclinic.org/health/diseases/14737-neuropathy#:~:text=Neuropathy%20is%20damage%20or%20dysfunction,body%20can%20be%20affected%20too.
  • Fledrich, R., Stassart, R. M., & Sereda, M. W. (2012). Murine therapeutic models for Charcot-Marie-Tooth (CMT) disease. Br Med Bull, 102, 89-113. doi:10.1093/bmb/lds010
  • Morena, J., Gupta, A., & Hoyle, J. C. (2019). Charcot-Marie-Tooth: From Molecules to Therapy. Int J Mol Sci, 20(14). doi:10.3390/ijms20143419
  • NIH. (2018). Charcot-Marie-Tooth Disease. US Deparment of Health and Human Services.
  • NORD. (2021). Charcot-Marie-Tooth Disease. Retrieved May 6, 2022 from https://rarediseases.org/rare-diseases/charcot-marie-tooth-disease/
  • Notterpek, L., Ryan, M. C., Tobler, A. R., & Shooter, E. M. (1999). PMP22 accumulation in aggresomes: implications for CMT1A pathology. Neurobiol Dis, 6(5), 450-460. doi:10.1006/nbdi.1999.0274

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