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| ====== Tay Sachs Disease ====== | ====== Tay Sachs Disease ====== | ||
| - | Tay Sachs is a fatal genetic disorder which occurs due to the deletion of an enzyme called beta-hexosaminidase A (also known as, HEXA), resulting in the accumulation of fatty acid GM2 ganglioside in neurons. This eventually leads to the progressive malfunctioning and degeneration of neurons. | + | Tay Sachs is a fatal genetic disorder which occurs due to the deletion of an enzyme called beta-hexosaminidase A (also known as, HEXA), resulting in the accumulation of fatty acid GM2 ganglioside in neurons. This eventually leads to the progressive malfunctioning and degeneration of neutrons (GHR, n.d.). |
| ===== Signs & Symptoms ===== | ===== Signs & Symptoms ===== | ||
| - | Tay Sachs affects the individual differently based on when their onset is: early (infantile and childhood ages) or late onset (adolescence and onwards). For early onset, the disease is not evident until about 6 months after the baby is born. Around 6 months, the child may show signs of reduced muscle function coming from progressive muscle weakness, twitching and muscle jerks. They will also have a greater sensitivity to sound, for example if they hear an unexpected sound, they will be startled (NORD, 2016). One characteristic sign of Tay Sachs is the development of “cherry red spots” found in the eyes. "Cherry red spots" are apparent in 90% of Tay Sachs disease cases (NORD, 2016). These spots are formed by macular degeneration and causes the choroid of the eye to be exposed. The choroid has blood vessels that supply blood to the retina. The child may also have a difficult time learning new motor movements such as holding eye contact (NORD, 2016). Children between ages 2-10 will experience a reduction in coordination, movement and intellectual abilities. They may also develop a variety of eye disorders such as optic atrophy which results in the loss of nerve function that delivers messages to brain to form images and retinitis pigmentosa which eventually results in the degeneration of the retina (NORD, 2016). Child may also experience a loss of speech and their speech will be slurred. | + | Tay Sachs affects the individual differently based on when their onset is: early (infantile and childhood ages) or late onset (adolescence and onwards). For early onset, the disease is not evident until about 6 months after the baby is born. Around 6 months, the child may show signs of reduced muscle function coming from progressive muscle weakness, twitching and muscle jerks. They will also have a greater sensitivity to sound, for example if they hear an unexpected sound, they will be startled (NORD, n.d). One characteristic sign of Tay Sachs is the development of “cherry red spots” found in the eyes. "Cherry red spots" are apparent in 90% of Tay Sachs disease cases (NORD, n.d.). These spots are formed by macular degeneration and causes the choroid of the eye to be exposed. The choroid has blood vessels that supply blood to the retina. The child may also have a difficult time learning new motor movements such as holding eye contact (NORD, n.d). Children between ages 2-10 will experience a reduction in coordination, movement and intellectual abilities. They may also develop a variety of eye disorders such as optic atrophy which results in the loss of nerve function that delivers messages to brain to form images and retinitis pigmentosa which eventually results in the degeneration of the retina (NORD, n.d.). Child may also experience a loss of speech and their speech will be slurred. |
| - | For late onset symptoms, the individual will experience a reduction of motor coordination resulting from muscle weakness and wasting, involuntary muscle contractions, twitches and tremors. May also experience slurred speech which significantly reduces their ability to interact with others. In addition, you see the sign of mood changes and deterioration in mental health (NORD, 2016). Overall, they’re unable to engage in and complete daily tasks such as driving, walking or interacting with others as one normally would be able to. | + | For late onset symptoms, the individual will experience a reduction of motor coordination resulting from muscle weakness and wasting, involuntary muscle contractions, twitches and tremors. May also experience slurred speech which significantly reduces their ability to interact with others. In addition, you see the sign of mood changes and deterioration in mental health (NORD, n.d.). Overall, they’re unable to engage in and complete daily tasks such as driving, walking or interacting with others as one normally would be able to. |
| <style center> | <style center> | ||
| <box width classes round white centre| **Tay Sachs Disease: Cherry Red Spots**> {{:cherry_red_spots.png|}}</box| Figure 1: Characteristic "cherry red spots" found in individuals with Tay Sachs disease. | <box width classes round white centre| **Tay Sachs Disease: Cherry Red Spots**> {{:cherry_red_spots.png|}}</box| Figure 1: Characteristic "cherry red spots" found in individuals with Tay Sachs disease. | ||
| - | (NORD, 2016).> | + | (NORD, n.d.).> |
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| - | <box 70% round | > {{:figure_from_gason_et_al_study.jpg|}} </box| Figure 5: Graph depicting the test uptake for TSD carrier status. (Gason et al.,2015).> | + | <box 62% round | > {{:figure_from_gason_et_al_study.jpg|}} </box| Figure 5: Graph depicting the test uptake for TSD carrier status. (Gason et al.,2015).> |
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| ===== Current Therapeutic Approach ===== | ===== Current Therapeutic Approach ===== | ||
| - | <box 20% round right | > {{:miglustat_.jpg|}} </box|Figure 6: Chemical Structure of Miglustat (synthetic analogue of D-glucose)> | + | <box 20% round right | > {{:miglustat_.jpg|}} </box|Figure 6: Chemical Structure of Miglustat (synthetic analogue of D-glucose). Modified from (DrugBank, 2016)> |
| - | An anticonvulsant is a medication used to control seizures (convulsions) or stop an ongoing series of seizures and is often used to treat individuals with Tay-Sachs but may not be effective in all people. An anticonvulsant called Miglustat, which is an analogue of D-glucose, is currently in clinical trials and has proven to be successful in tay-sachs induced mouse models. | + | An anticonvulsant is a medication used to control seizures (convulsions) or stop an ongoing series of seizures and is often used to treat individuals with Tay-Sachs but may not be effective in all people. An anticonvulsant called Miglustat, which is an analogue of D-glucose, is currently in clinical trials and has proven to be successful in tay-sachs induced mouse models (Osher et al., 2011). |
| - | Another strategy is substrate deprivation which utilizes an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In a recent study, mouse models with Gaucher disease were treated with the inhibitor N-butyldeoxynojirimycin. The treated mice showed delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease. | + | Another strategy is substrate deprivation which utilizes an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In a recent study, mouse models with Gaucher disease were treated with the inhibitor N-butyldeoxynojirimycin. The treated mice showed delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease (Jeyakumar et al., 1999) |
| - | Because of the potential of feeding difficulties, infants should be monitored for nutritional status and proper hydration. In addition to nutritional support and supplementation, a feeding tube may be necessary to help prevent food, liquid or other foreign material from accidentally going into the lungs. | + | Because of the potential of feeding difficulties, infants should be monitored for nutritional status and proper hydration. In addition to nutritional support and supplementation, a feeding tube may be necessary to help prevent food, liquid or other foreign material from accidentally going into the lungs (Osher et al., 2011). |
| - | <box 37% round | > {{:feeding_tube_diagram.jpg|}} </box|Figure 7: Feeding tube used for children to prevent food from entering the lungs> | + | <box 37% round | > {{:feeding_tube_diagram.jpg|}} </box|Figure 7: Feeding tube used for children to prevent food from entering the lungs. Modified from (ThisAbility, 2016)> |
| ===== Investigational Therapies ===== | ===== Investigational Therapies ===== | ||
| - | Further investigation into drug treatments and substrate reduction therapies would be necessary to find a “cure” to this fatal disease. Research is being done to understand and evaluate the effects of different levels of psychosocial support to the affected child and the family. A drug called pyrimethamine has been tried as a treatment for Tay-Sachs disease. Affected individuals who took the medication showed increased activity of hexosaminidase A. However, this increased activity did not lead to any noticeable improvement in neurological or psychiatric symptoms. Therefore, more research is necessary to determine whether pyrimethamine has any significant therapeutic role. | + | <box 40% round right| > {{:ert_44444.jpg|}} </box| Figure 8: Investigational Therapies (including Enzyme Replacement Therapy and Substrate Reduction Therapy) being studied for the treatment of Tay-Sachs disease. Modified from (Sánchez-Fernández et al., 2016)> |
| + | |||
| + | Further investigation into drug treatments and substrate reduction therapies would be necessary to find a “cure” to this fatal disease. Research is being done to understand and evaluate the effects of different levels of psychosocial support to the affected child and the family. A drug called pyrimethamine has been tried as a treatment for Tay-Sachs disease. Affected individuals who took the medication showed increased activity of hexosaminidase A. However, this increased activity did not lead to any noticeable improvement in neurological or psychiatric symptoms. Therefore, more research is necessary to determine whether pyrimethamine has any significant therapeutic role (Osher et al., 2011). | ||
| **Enzyme Replacement Therapy:** | **Enzyme Replacement Therapy:** | ||
| - | Research is ongoing to develop enzyme replacement therapy (ERT) for Tay-Sachs disease which involves replacing a missing enzyme in individuals who are deficient or lack a particular enzyme. Synthetic versions of missing enzymes have been developed and used to treat individuals with other lysosomal storage diseases including Hurler syndrome and Gaucher disease. However, ERT has not proven successful in people with Tay-Sachs disease. One issue is the inability to find a way for the replacement enzyme to cross the blood-brain barrier. | + | Research is ongoing to develop enzyme replacement therapy (ERT) for Tay-Sachs disease which involves replacing a missing enzyme in individuals who are deficient or lack a particular enzyme. Synthetic versions of missing enzymes have been developed and used to treat individuals with other lysosomal storage diseases including Hurler syndrome and Gaucher disease. However, ERT has not proven successful in people with Tay-Sachs disease. One issue is the inability to find a way for the replacement enzyme to cross the blood-brain barrier (Cachón-González et al., 2006). |
| **Gene Therapy:** | **Gene Therapy:** | ||
| - | Gene therapy is also being studied as another possible approach to therapy where the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent the development and progression of the disease. Given the permanent transfer of the normal gene, which can produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” | + | Gene therapy is also being studied as another possible approach to therapy where the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent the development and progression of the disease. Given the permanent transfer of the normal gene, which can produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” (Cachón-González et al., 2006) |
| **Chaperone Therapy:** | **Chaperone Therapy:** | ||
| - | Chaperone therapy is also being studied for Tay-Sachs disease which involves very small molecules that attach to newly-created HexA enzymes, before the mutated enzymes are broken down, and guides them to the lysosome, where the enzymes can perform their normal function. Such a molecule can also cross the blood-brain barrier. This therapy is only in initial stages of study, and more research will be necessary to determine its long-term safety and effectiveness. | + | Chaperone therapy is also being studied for Tay-Sachs disease which involves very small molecules that attach to newly-created HexA enzymes, before the mutated enzymes are broken down, and guides them to the lysosome, where the enzymes can perform their normal function. Such a molecule can also cross the blood-brain barrier. This therapy is only in initial stages of study, and more research will be necessary to determine its long-term safety and effectiveness (Cachón-González et al., 2006). |
| ===== Conclusion ===== | ===== Conclusion ===== | ||
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| ===== References ===== | ===== References ===== | ||
| - | 1. About NTSAD. (n.d.). Retrieved from https://www.ntsad.org/index.php/about | + | 1. NTSAD. (n.d.). About NTSAD. Retrieved from https://www.ntsad.org/index.php/about |
| 2. Bergeron, S. (1997). Tay-Sachs. Retrieved from http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/S.%20Bergeron.html | 2. Bergeron, S. (1997). Tay-Sachs. Retrieved from http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/S.%20Bergeron.html | ||
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| 14. Neudorfer, O., Pastores, G.M., Zeng, B.J., Gianutsos, J., Zaroff, C.M., & Kolodny, E.H. (2005). Late-onset Tay-Sachs disease: Phenotypic characterization and genotypic correlations in 21 affected patients. Genetics in Medicine, 7, 119-123. | 14. Neudorfer, O., Pastores, G.M., Zeng, B.J., Gianutsos, J., Zaroff, C.M., & Kolodny, E.H. (2005). Late-onset Tay-Sachs disease: Phenotypic characterization and genotypic correlations in 21 affected patients. Genetics in Medicine, 7, 119-123. | ||
| - | 15. NORD. (2016). Tay Sachs Disease. Retrievedfrom https://rarediseases.org/rare-diseases/tay-sachs-disease/ | + | 15. NORD.(n.d.).Tay Sachs Disease. Retrieved from https://rarediseases.org/rare-diseases/tay-sachs-disease/ |
| 16. Osher, E., Fattal-Valevski, A., Sagie, L., Urshanski, N., Amir-Levi, Y., Katzburg, S., ... & Navon, R. (2011). Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs. Molecular genetics and metabolism, 102(3), 356-363. | 16. Osher, E., Fattal-Valevski, A., Sagie, L., Urshanski, N., Amir-Levi, Y., Katzburg, S., ... & Navon, R. (2011). Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs. Molecular genetics and metabolism, 102(3), 356-363. | ||
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| 19. Sandhoff, K., & Harzer, K. (2013). Gangliosides and gangliosidoses: Principles of molecular and metabolic pathogenesis. Journal of Neuroscience, 33(25), 10195-10208. | 19. Sandhoff, K., & Harzer, K. (2013). Gangliosides and gangliosidoses: Principles of molecular and metabolic pathogenesis. Journal of Neuroscience, 33(25), 10195-10208. | ||
| - | 20. Tay Sachs Disease. (n.d.). Retrieved from https://rarediseases.org/rare-diseases/tay-sachs-disease/ | + | 20. Sánchez-Fernández, E. M., Fernández, J. M. G., & Mellet, C. O. (2016). Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, G M1-gangliosidosis and Fabry diseases. Chemical Communications, 52(32), 5497-5515. |
| - | + | ||
| - | 21. Tay Sachs disease (2017). Genetics Home Reference. Retrieved from https://ghr.nlm.nih.gov/condition/tay-sachs-disease | + | |
| - | 22. Tuck, E., & Cavalli, V. (2010). Roles of membrane trafficking in nerve repair and regeneration. Communicative & Integrative Biology, 3(3), 209-214. | + | 21. Tuck, E., & Cavalli, V. (2010). Roles of membrane trafficking in nerve repair and regeneration. Communicative & Integrative Biology, 3(3), 209-214. |
| - | 23. Walkley, S.U., Siegel, D.A., & Dobrenis, K. (1995). GM2 ganglioside and pyramidal neuron dendritogenesis. Neurochemical Research, 20(11), 1287-1299. | + | 22. Walkley, S.U., Siegel, D.A., & Dobrenis, K. (1995). GM2 ganglioside and pyramidal neuron dendritogenesis. Neurochemical Research, 20(11), 1287-1299. |
| - | 24. Withrock, I. C. et. al. (2015). Genetic diseases conferring resistance to infectious diseases. Genes & Diseases, 2(3): 247-254. doi: 10.1016/j.gendis.2015.02.008 http://www.sciencedirect.com/science/article/pii/S2352304215000239 | + | 23. Withrock, I. C. et. al. (2015). Genetic diseases conferring resistance to infectious diseases. Genes & Diseases, 2(3): 247-254. doi: 10.1016/j.gendis.2015.02.008 http://www.sciencedirect.com/science/article/pii/S2352304215000239 |
| - | 25. Yu, R.K., Bieberich, E., Xia, T., & Zeng, G. (2004). Regulation of ganglioside biosynthesis in the nervous system. Journal of Lipid Research, 45(5), 783-793. | + | 24. Yu, R.K., Bieberich, E., Xia, T., & Zeng, G. (2004). Regulation of ganglioside biosynthesis in the nervous system. Journal of Lipid Research, 45(5), 783-793. |
| - | 26. Yu, R.K., Tsai, Y., & Ariga, T. (2012). Functional roles of gangliosides in neurodevelopment – An overview of recent advances. Neurochemical Research, 37(6), 1230-1244. | + | 25. Yu, R.K., Tsai, Y., & Ariga, T. (2012). Functional roles of gangliosides in neurodevelopment – An overview of recent advances. Neurochemical Research, 37(6), 1230-1244. |
| - | 27. Yu, R.K., Tsai, Y., Ariga, T., & Yanagisawa, M. (2011). Structures, biosynthesis, and functions of gangliosides – An overview. Journal of Oleo Science, 60(10), 537-544. | + | 26. Yu, R.K., Tsai, Y., Ariga, T., & Yanagisawa, M. (2011). Structures, biosynthesis, and functions of gangliosides – An overview. Journal of Oleo Science, 60(10), 537-544. |
