Biology of CMT4J
How CMT4J Affects the Body
The severity and timing of when signs and symptoms of A rare inherited peripheral neuropathy often characterized by rapidly progressive, asymmetrical upper and lower extremity weakness, muscle atrophy leading to handicap, and respiratory issues with no available treatment. CMT4J is a recessive subtype of CMT caused by a variant, also referred to as a mutation, in the FIG4 gene. begin to show in individuals can vary. Some patients show mild signs, while others have a more severe disability that requires more support. CMT4J mainly causes problems with motor skills, such as weakness in the limbs and muscles. Individuals with CMT4J gradually or rapidly lose both The ability to make large, general movements, such as waving an arm or lifting a leg. This requires proper coordination and function of muscle, bones, and nerves. and The coordination of muscles, bones, and nerves to produce small, exact movements. An example of fine motor control is picking up a small item with the index finger (pointer finger or forefinger) and thumb..
Science Behind CMT4J
CMT4J affects both motor and sensory nerves, so understanding how the nervous system functions is essential. The nervous system consists of both motor A nerve cell that receives and sends electrical signals from sensory cells and other neurons over long distances within the body. These signals are sent to muscle neurons and other neurons. and sensory neurons. One set of nerves delivers messages from the brain to the rest of the body, and the other brings messages from the rest of the body back to the brain.
Motor neurons send messages from the brain through the spinal cord to the lower muscles of the body. Sensory neurons send messages from the sensory input to the spinal cord upward to the brain. The peripheral nervous system (the nervous system outside of the brain and spinal cord) affects both motor and sensory nerve fibers. These nerves have an inner coating, the Long and single nerve-cell process that usually conducts impulses away from the cell body. core, which is wrapped with a protective insulation called the A soft white material that forms a thick layer around the axons of some neurons and is composed chiefly of lipids (such as cerebroside and cholesterol), water, and smaller amounts of protein. sheath. The myelin sheath’s job is to protect the axon and speed transmission of signals through the nerves.
In individuals living with CMT, these nerves are damaged due to mutated genes that result in both motor symptoms (weakness and muscle wasting) and sensory symptoms (numbness).
All subtypes of CMT4 are inherited in an Inheritance characteristic where a gene is located on a numbered, non-sex chromosome. These are found on one of the 22 pairs of (44 total) autosomal chromosomes in a human body where DNA is stored. This is one of several ways that a trait, disorder, or disease can be passed down through families. These chromosomes are not the sex (X or Y) chromosomes. recessive pattern. Autosomal recessive describes one of several ways that a disorder or disease is passed down through families. An autosomal recessive disorder occurs when a child inherits two copies of an abnormal gene, one from the mother and one from the father. The biological parents often have no symptoms of disease because the one functional gene is able to compensate for the defective gene. Two healthy people, who are carriers, can have multiple children with a genetic disorder even though they do not show symptoms themselves.
In the case of CMT4J, a A variant is a change in DNA. A variant may or may not cause disease. The following modifiers describe the variant: (i) pathogenic, (ii) likely pathogenic, (iii) uncertain significance, (iv) likely benign, or (v) benign depending on whether or not the variant causes disease. For example, a “pathogenic variant” may cause disease. The term “variant” has replaced the term “mutation.” in the The FIG4 gene is the only gene in which pathogenic variants are known to cause CMT4J. gene must be inherited from both parents for a child to inherit the CMT4J disease.
Healthy FIG4 Gene
When functioning normally, FIG4 To specify the genetic instructions to make a protein. a protein that aids in the survival of neurons and regulates the transport of waste within the cells.
When there is a FIG4 variant present, the body’s ability to move waste through cells is impaired and waste builds up. This buildup of waste slows the nerves’ ability to do their job of sending messages and leads to nerve damage, classifying CMT4J as a Refers to the loss or damage to the myelin or protective covering of the nerve tissue. This damage leads to slowed nerve impulses, causing neurological problems.. Demyelination leads to weakness and sometimes numbness or pain.
- Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., … Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: a severe Nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness in various parts of the body typically beginning in the hands or feet, then getting worse over time. caused by A mutation is any inherited genetic change. The term “mutation” is being replaced by the term “variant.” in the PI(3,5)P₂ phosphatase FIG4. Brain: a journal of neurology, 134(Pt 7), 1959–1971. doi:10.1093/brain/awr148. Retrieved June 26, 2019, from link.
- Field research conducted by Neurogene and Ten Bridge Communications, July 2019.
- Novais, E. N., Bixby, S. D., Rennick, J., Carry, P. M., Kim, Y. J., & Millis, M. B. (2014). Hip dysplasia is more severe in The most common inherited motor and sensory neuropathies, composed of a group of pathologically and genetically distinct subtypes ranging from slowly to rapidly progressive disease. CMT is further classified based on the genetic mutation or variant involved – for instance, CMT4A, CMT4B, etc. disease than in developmental dysplasia of the hip. Clinical orthopaedics and related research, 472(2), 665–673. doi:10.1007/s11999-013-3127-z. Retrieved June 26, 2019, from link.
- Hatakeyama, S., Suzuki, J., Murukami, T., Nagaoka, T., Suzuki, K., Sakamato, K., … Uchigata, M. (2000). [Respiratory failure due to diaphragmatic dysfunction in Charcot-Marie-Tooth disease: A case report]. Journal of the Japanese Respiratory Society, 38(8), 637-641. Retrieved June 26, 2019, from link.
- Bharadwaj, R., Cunningham, K. M., Zhang, K., & Lloyd, T. E. (2015). FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Human Molecular Genetics, 25(4), 681-692. doi:10.1093/hmg/ddv505. Retrieved September 24, 2019, from link.
- Haidar, M., & Timmerman, V. (2017). Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies. Frontiers in Molecular Neuroscience, 10. doi:10.3389/fnmol.2017.00143. Retrieved September 24, 2019, from link.
- Types of CMT. (n.d.). Retrieved June 26, 2019, from link.
- Fliesler, N. (2017, March 6). With no time to lose, parents drive CMT4J gene therapy forward. Retrieved June 26, 2019, from link.
- Lewis, R. (2017, February 23). Rare Disease Day 2017: Talia’s Story [Web log post]. Retrieved June 26, 2019, from link.
- Li, J. (1993). Charcot-Marie-Tooth Neuropathy Type 4J. Retrieved June 26, 2019, from link.
- About CMT4J. (n.d.). Retrieved June 26, 2019, from link.
- Orengo, J. P., Khemani, P., Day, J. W., Li, J., & Siskind, C. E. (2018). Charcot Marie Tooth disease type 4J with complex central nervous system features. Annals of Clinical and Translational Neurology, 5. doi:10.1002/acn3.525. Retrieved on June 26, 2019, from link.