This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is Hereditary Spastic Paraplegia (HSP)?
Hereditary Spastic Paraplegia (HPS) is a rare group of neurological disorders associated with progressive weakness and extreme spasticity of the lower extremities. In total, there is 90 different types of HSP identified but only 50 have known genetic causes [2]. Dependent on the type of mutation that has occurred, the form of HSP may vary. An autosomal dominant form of HSP known as SPG10 result from mutations in the KIF5A gene [2,3,5], which leads to axonal degeneration in the corticospinal tract [1,2,3,5]. Other forms of HSP can have complex genetics, either being autosomal dominant, X-linked recessive, or autosomal recessive[8]; each type of HSP varying based on the type of mutation that is present as well as the affected gene. This group of diseases was first described in 1883 by Strümpell and was later explored in more detail by Lorrain giving the set of diseases yet another name, Strümpell-Lorrain Syndrome[1].
HSP can be put into two different categories dependent on the severity of the case: Uncomplicated Spastic Paraplegia - neurological impairment limited to only the lower body Complicated Spastic Paraplegia - neurological impairment in lower body as well as other systems causing additional symptoms (impaired vision, cognitive impairment, etc.)[2] |
Pure HSP Symptoms[2]:
Complex HSP Symptoms[8]:
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The Effect of HSP on the Neurological System
Structure of a Motor Neuron:
All neurons have a cell body, dendrites which receive messages from other neurons, and an axon in which signals are transmitted down. For upper motor neurons, the cell body can be found in the motor cortex of the brain which can be seen on the right. The axons of these neurons then relay messages to the lower motor neurons in the brainstem and spinal cord. In turn the signal is then transmitted to muscles to carry out the desired action[2]. Cause of HSP Symptoms: Hereditary Spastic Paraplegia is caused by degeneration of the upper motor neurons which control the voluntary movement of muscles. When degeneration occurs, the messages that are intended for the muscles can not be received resulting eventually in spasticity and weakness. Typically for HSP, the lower muscles are affected the most because degeneration mainly occurs at the ends of the longest neurons. This is a slow process that eventually results in symptoms.[1] Treatment: Currently there is no real treatment for HSP. Some individuals take medications to help aid with the spasticity of muscles and other symptoms that arise from the genetic disorder. Typically individuals require some sort of physical therapy to help cope with the lack of muscle strength. SPF is the only organization that exists that is dedicated to researching a cure for the disease[1]. |
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KIF5A and SPG10
SPG10 is an autosomal dominant form of HSP that occurs as result of mutations in the KIF5A gene [6,4,8]. When unaffected by mutations KIF5A has been observed to carry organelles and vesicles anterograde and retrograde through the axon, acting in a multisubunit complex that functions as a kinesin motor [4,7,8]. Previous studies have shown that KIF5A aids in the transportation of both mitochondria and neurofilaments within the cell. Mutation of this gene affects transportation of cargo across the axon and results in its degeneration [5]. Typically a mutated KIF5A is a result of a missense mutation that occurs at the motor domain. This mutation prevents the stimulation of the motor ATPase by microtubule binding [4].
The KIF5A gene is located on the long arm of chromosome 12 at position 13.1 between 57549992 bp and 57586633 bp [4].
The KIF5A gene is located on the long arm of chromosome 12 at position 13.1 between 57549992 bp and 57586633 bp [4].
References
[1] Hereditary Spastic Paraplegia (2016, April). Retrieved January 31, 2019, from https://rarediseases.info.nih.gov/diseases/6637/hereditary-spastic-paraplegia
[2] Spastic Paraplegia Foundation. Retrieved January 31, 2019, from https://sp-foundation-org.presencehost.net/who_we_are/overview.html
[3] Paik, N (2019, January). Hereditary Spastic Paraplegia. Retrieved January 31, 2019, from https://emedicine.medscape.com/article/306713-overview
[4] Reid, E (2002, November). A Kinesin Heavy Chain (KIF5A) Mutation in Hereditary Spastic Paraplegia (SPG10). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC385095/
[5] Cuchanski, M., & Baldwin, K. J. (2018). Mutation in KIF5A c.610C>T Causing Hereditary Spastic Paraplegia with Axonal Sensorimotor Neuropathy. Case reports in neurology, 10(2), 165-168. doi:10.1159/000490456
[6] Musumeci, O., Bassi, M.T., Mazzeo, A. et al. Neurol Sci (2011) 32: 665. https://doi.org/10.1007/s10072-010-0445-8
[7] Filosto, M., Piccinelli, S. C., Palmieri, I., Necchini, N., Valente, M., Zanella, I., Biasiotto, G., Lorenzo, D. D., Cereda, C., … Padovani, A. (2018). A Novel Mutation in the Stalk Domain of KIF5A Causes a Slowly Progressive Atypical Motor Syndrome. Journal of clinical medicine, 8(1), 17. doi:10.3390/jcm8010017
[8] Kawaguchi, K. (2013). Role of Kinesin-1 in the Pathogenesis of SPG10, a Rare Form of Hereditary Spastic Paraplegia. The Neuroscientist, 19(4), 336–344. https://doi.org/10.1177/1073858412451655
[1] Hereditary Spastic Paraplegia (2016, April). Retrieved January 31, 2019, from https://rarediseases.info.nih.gov/diseases/6637/hereditary-spastic-paraplegia
[2] Spastic Paraplegia Foundation. Retrieved January 31, 2019, from https://sp-foundation-org.presencehost.net/who_we_are/overview.html
[3] Paik, N (2019, January). Hereditary Spastic Paraplegia. Retrieved January 31, 2019, from https://emedicine.medscape.com/article/306713-overview
[4] Reid, E (2002, November). A Kinesin Heavy Chain (KIF5A) Mutation in Hereditary Spastic Paraplegia (SPG10). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC385095/
[5] Cuchanski, M., & Baldwin, K. J. (2018). Mutation in KIF5A c.610C>T Causing Hereditary Spastic Paraplegia with Axonal Sensorimotor Neuropathy. Case reports in neurology, 10(2), 165-168. doi:10.1159/000490456
[6] Musumeci, O., Bassi, M.T., Mazzeo, A. et al. Neurol Sci (2011) 32: 665. https://doi.org/10.1007/s10072-010-0445-8
[7] Filosto, M., Piccinelli, S. C., Palmieri, I., Necchini, N., Valente, M., Zanella, I., Biasiotto, G., Lorenzo, D. D., Cereda, C., … Padovani, A. (2018). A Novel Mutation in the Stalk Domain of KIF5A Causes a Slowly Progressive Atypical Motor Syndrome. Journal of clinical medicine, 8(1), 17. doi:10.3390/jcm8010017
[8] Kawaguchi, K. (2013). Role of Kinesin-1 in the Pathogenesis of SPG10, a Rare Form of Hereditary Spastic Paraplegia. The Neuroscientist, 19(4), 336–344. https://doi.org/10.1177/1073858412451655
Alex Myers
[email protected] Last Updated: February 5th 2019 Course Webpage: www.genetics564.weebly.com |
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