Genetic Disorders: Tay-Sachs Disease
WHAT ARE GENETIC DISORDERS?
A genetic disorder is a life long illness caused by an abnormality in a human's DNA. These abnormalities range from being a small mutation in a gene that can cause small developmental hindrance to the alteration of an entire chromosome or set of chromosomes that can cause severe physical and mental impairments.
Genetic disorders themselves are divided into levels: Single Gene Disorders, Chromosome Abnormalities and Multifactorial Disorders. A Single Gene disorder results when a mutation occurs in the protein production of a single gene, leading to an alteration in the gene or its deletion. A Chromosome Abnormality occurs when an entire chromosome or a significant portion of it is either missing, unnecessarily duplicated or altered in some way. Multifactorial Disorders are the result of various mutations taking place in multiple genes in addition to environmental causes (2). Tay-Sachs disease is an example of a single gene disorder.
A genetic disorder is a life long illness caused by an abnormality in a human's DNA. These abnormalities range from being a small mutation in a gene that can cause small developmental hindrance to the alteration of an entire chromosome or set of chromosomes that can cause severe physical and mental impairments.
Genetic disorders themselves are divided into levels: Single Gene Disorders, Chromosome Abnormalities and Multifactorial Disorders. A Single Gene disorder results when a mutation occurs in the protein production of a single gene, leading to an alteration in the gene or its deletion. A Chromosome Abnormality occurs when an entire chromosome or a significant portion of it is either missing, unnecessarily duplicated or altered in some way. Multifactorial Disorders are the result of various mutations taking place in multiple genes in addition to environmental causes (2). Tay-Sachs disease is an example of a single gene disorder.
HISTORY OF TAY SACHS DISEASE
Cherry-red spot first discovered by Dr. Tay. (7)
Tay Sachs Disease is named after British ophthalmologist Warren Tay who had a patient in 1881 with a cherry red spot on the retina of the eye and Bernard Sachs, a New York neurologist at Mount Sinai Hospital whose work provided the first scientific description of the cellular changes that take place throughout the development of Tay-Sachs disease (3). Additionally, Dr. Sachs discovered the hereditary nature of the disorder and noted how most children afflicted with Tay-Sachs were of Eastern European Jewish origin (3).
In August of 1969, Dr. Shintaro Okada and Dr. John S. O'Brien published their discovery of the Hexosaminidase A deficiency in Tay-Sachs Disorder. This discovery lead to the first Tay-Sachs community screening that took place in Bethesda, Maryland in May 1971 (3).
In August of 1969, Dr. Shintaro Okada and Dr. John S. O'Brien published their discovery of the Hexosaminidase A deficiency in Tay-Sachs Disorder. This discovery lead to the first Tay-Sachs community screening that took place in Bethesda, Maryland in May 1971 (3).
Watch this segment on Tay Sachs Disease from PBS' NOVA:
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Watch Cracking the Code of Life on PBS. See more from NOVA.
Autosomal Recessive Pedigree (10)
GENETIC MUTATION OF TAY SACHS DISEASE
Tay Sachs Disease is an autosomal recessive disease and is caused by single defective gene on chromosome 15 (4). Tay Sachs can only be inherited if both parents are unaffected, heterozygous carriers. If both the mother and the father are carriers of the defective Tay-Sachs gene, a child has a 25% chance of developing Tay Sachs. If only one parent passes the defective gene to the child, the child is becomes a carrier. He or she will not develop the disease, but they may pass the disease to their children (4).
Anyone can be a carrier of Tay-Sachs, but the disease is most common in Ashkenazi Jews. About 1 Askenazi Jew in every 27 carries the Tay-Sachs gene. Ashkenazi Jews have European heritage and are prevalent in many eastern European countries. Ashkenazi Jews make up approximately 80% of the world's Jewish population (5).
Tay Sachs Disease is an autosomal recessive disease and is caused by single defective gene on chromosome 15 (4). Tay Sachs can only be inherited if both parents are unaffected, heterozygous carriers. If both the mother and the father are carriers of the defective Tay-Sachs gene, a child has a 25% chance of developing Tay Sachs. If only one parent passes the defective gene to the child, the child is becomes a carrier. He or she will not develop the disease, but they may pass the disease to their children (4).
Anyone can be a carrier of Tay-Sachs, but the disease is most common in Ashkenazi Jews. About 1 Askenazi Jew in every 27 carries the Tay-Sachs gene. Ashkenazi Jews have European heritage and are prevalent in many eastern European countries. Ashkenazi Jews make up approximately 80% of the world's Jewish population (5).
Tay-Sachs Chart (11)
WHAT TAY SACHS DOES
Tay Sachs occurs when just one specific letter goes wrong in the DNA chain. That one letter means the body cannot properly create the enzyme Hexosaminidase A, which is a vital hyrdolytic enzyme found in lysosomes which breaks down phospholipids (5). When hexosaminidase A is not functioning properly, the lipids accumulate in the brain and fat builds up, swells the brain, and strangles critical brain cells. (8).
Most Tay–Sachs mutations do not affect protein active sites, Instead, they cause incorrect folding or disable intracellular transport (5).
For more information on how Tay Sacs affects children, follow through the animation below by clicking the red CONTINUE button:
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Tay Sachs occurs when just one specific letter goes wrong in the DNA chain. That one letter means the body cannot properly create the enzyme Hexosaminidase A, which is a vital hyrdolytic enzyme found in lysosomes which breaks down phospholipids (5). When hexosaminidase A is not functioning properly, the lipids accumulate in the brain and fat builds up, swells the brain, and strangles critical brain cells. (8).
Most Tay–Sachs mutations do not affect protein active sites, Instead, they cause incorrect folding or disable intracellular transport (5).
For more information on how Tay Sacs affects children, follow through the animation below by clicking the red CONTINUE button:
(12)
Symptoms of Tay Sachs Disease (9)
SYMPTOMS AND DIAGNOSIS
Tay-Sachs can be classified into three forms: infantile, juvenile, and adult. Those effected are classified depending on the symptoms and when they first appear. Tay-Sachs is most common in the infantile form. In this form, nerve damage usually begins while the baby is still in the womb and symptoms start to appear when the child is 3 to 6 months old. The disease tends to get worse very quickly, and most children die by age 4 or 5. Adult Tay-Sachs disease is very rare. Carriers of Tay–Sachs and affected children can be identified by a blood test that measures hexosaminidase A activity. (5)
Symptoms of Tay-Sachs include:
Tay-Sachs can be classified into three forms: infantile, juvenile, and adult. Those effected are classified depending on the symptoms and when they first appear. Tay-Sachs is most common in the infantile form. In this form, nerve damage usually begins while the baby is still in the womb and symptoms start to appear when the child is 3 to 6 months old. The disease tends to get worse very quickly, and most children die by age 4 or 5. Adult Tay-Sachs disease is very rare. Carriers of Tay–Sachs and affected children can be identified by a blood test that measures hexosaminidase A activity. (5)
Symptoms of Tay-Sachs include:
- Deafness
- Decreased eye contact, blindness
- Decreased muscle tone (loss of muscle strength)
- Dementia
- Increased startle reaction
- Irritability
- Listlessness
- Loss of motor skills
- Paralysis or loss of muscle function
- Seizures
- Slow growth.
CURRENT RESEARCH FOR A CURE
No treatment or cure for Tay-Sachs disease has been found to date but every day, research is being furthered towards a potential treatment. Research is being done heavily in the realms of gene therapy, pharmacological/molecular chaperone therapy, and stem cell research (3).
No treatment or cure for Tay-Sachs disease has been found to date but every day, research is being furthered towards a potential treatment. Research is being done heavily in the realms of gene therapy, pharmacological/molecular chaperone therapy, and stem cell research (3).
A representation of the way gene therapy occurs (1)
Research in the field of gene therapy is so optimistic that the concept of opening gene therapy clinical trials for Tay-Sachs victims could begin as early as March 2013 (3). Despite these positive predictions, gene therapy is not without its challenges. Some of the hurdles hindering the further progress of gene therapy include the difficulty of creating effective vectors to deliver the improved gene to the brain, the need to introduce the gene into a substantial amount of cells for it to be in any way effective, the difficulties of inserting said gene into the appropriate brain cell and the dangerous possibility of cancer as a result of the gene insertion into the cell's chromosomes (3).
Pyrimethamine, a medication commonly used in the treatment and prevention of malaria, has been found to increase ß-hexosaminidase activity, slowing the progression of Late-Onset and Juvenile Tay-Sachs disease (6). It is being investigated as a possibility of being a pharmacological/molecular chaperone for Tay-Sachs. However, only adults with specific mutations known to respond to pyrimethamine are able to be helped by this therapy (3). The main hurdle facing the furthering of this research is due to the lack of biomarkers and the belief that with the wrong dose, the drug may in fact reduce enzyme function, hurting the patient more (3).
Stem Cell Therapy has been developed to the point that potential treatments that could cure illnesses such as Tay-Sachs are being tested on lab animals . Some have already been developed to the point of being used in clinical trials. However, like any potential cure, stem cell therapy faces challenges of its own. Some of the various risks include the real threat that an immune response will lead to the rejection of the stem cells, the risk of transmission of donor-related illnesses that may have been residing in the cells (3).
Pyrimethamine, a medication commonly used in the treatment and prevention of malaria, has been found to increase ß-hexosaminidase activity, slowing the progression of Late-Onset and Juvenile Tay-Sachs disease (6). It is being investigated as a possibility of being a pharmacological/molecular chaperone for Tay-Sachs. However, only adults with specific mutations known to respond to pyrimethamine are able to be helped by this therapy (3). The main hurdle facing the furthering of this research is due to the lack of biomarkers and the belief that with the wrong dose, the drug may in fact reduce enzyme function, hurting the patient more (3).
Stem Cell Therapy has been developed to the point that potential treatments that could cure illnesses such as Tay-Sachs are being tested on lab animals . Some have already been developed to the point of being used in clinical trials. However, like any potential cure, stem cell therapy faces challenges of its own. Some of the various risks include the real threat that an immune response will lead to the rejection of the stem cells, the risk of transmission of donor-related illnesses that may have been residing in the cells (3).
CRITICAL THINKING QUESTIONS
1. Based on the information provided in the glossary and what you know about single gene disorders, identify and explain another single gene disorder.
2. What therapy coping methods would you suggest for a family dealing with the fact that their child has been diagnosed with Tay-Sachs?
1. Based on the information provided in the glossary and what you know about single gene disorders, identify and explain another single gene disorder.
2. What therapy coping methods would you suggest for a family dealing with the fact that their child has been diagnosed with Tay-Sachs?
References
- GeneTherapy. Digital image. Common Health: Reform and Reality. N.p., n.d. Web. <http://commonhealth.wbur.org/2011/11/tay-sachs-human-trial>.
- Genetic Science Learning Center. "What are Genetic Disorders?."Learn.Genetics 28 November 2012 <http://learn.genetics.utah.edu/content/disorders/whataregd/>
- "History of Tay-Sachs Disease." National Tay-Sachs and Allied Diseases. National Tay-Sachs & Allied Diseases Association, n.d. Web. 28 Nov. 2012. <http://www.ntsad.org/index.php/tay-sachs/history>
- Sheth, Kevin, MD. "Tay-Sachs Disease." A.D.A.M Medical Encyclopedia. N.p., Nov. 2010. Web. Nov. 2012. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002390/>.
- "Tay-Sachs Disease." Wikipedia. N.p., n.d. Web. <http://en.wikipedia.org/wiki/Tay%E2%80%93Sachs_disease>.
- "Pyrimethamine." Wikipedia. Wikimedia Foundation, 23 Nov. 2012. Web. 28 Nov. 2012. <http://en.wikipedia.org/wiki/Pyrimethamine>.
- Trobe, M.D., Jonathan. Tay-SachsUMich. Digital image. The Eyes Have It. University of Michigan Kellogg Eye Center, n.d. Web. <http://www.kellogg.umich.edu/theeyeshaveit/congenital/tay-sachs.html>.
- "Cracking the Code of Life." PBS. PBS, n.d. Web. 30 Nov. 2012. <http://www.pbs.org/wgbh/nova/body/cracking-the-code-of-life.html>.
- "Index." Index. N.p., n.d. Web. 30 Nov. 2012. <http://www.telmeds.org/wp-content/uploads/2011/05/>.
- Wikipedia. Wikimedia Foundation, n.d. Web. 30 Nov. 2012. <http://en.wikipedia.org/wiki/File:Autorecessive.svg>.
- "Tay-Sachs Disease." N.p., n.d. Web. 30 Nov. 2012. <http://taysachsdisease.wikidot.com/>.
- "Tay-Sachs: What Causes It?" Tay-Sachs: What Causes It? N.p., n.d. Web. 03 Dec. 2012. <http://yourgenesyourhealth.org/tay/cause.htm>.