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Tay Sach's Disease

What is Tay-Sachs Disease?

Tay-Sachs disease is a fatal neurological genetic disorder that effects lipid storage. Individuals with Tay-Sachs are deficient in an enzyme named beta-hexosaminidase A (Hex-A). The role of Hex-A in the body is to catalyze the breakdown of gangliosides (GM2), an acidic fatty substance within cells. During neural development, gangliosides are produced and biodegraded quickly. However, in babies that are missing Hex-A, over time gangliosides build up in nerve cells and rapid deterioration of physical and mental functioning results. Tay-Sachs is progressive; infants my appear to be developing normally for the first months of life but as GM2 accumulates in nerve cells, the infant quickly becomes symptomatic.


The Biology of Tay-Sachs

Tay-Sachs is caused by a mutation in the HEX A gene found on chromosome 15. This gene codes for the enzyme Hex A, which is found in the lysosomes of cells. In the lysosomes it serves to break down the lipid, ganglioside GM2. If Hex A does not function properly then GM2 accumulates in the nerve cells during development, because it is not being broken down. Accumulation eventually causes nerve cell death. 

Pale pink cells are abnormal, enlarged neurons


Luxol fast blue stain highlights the large swollen neurons in Tay-Sachs disease

Electron micrograph that shows the buildup of gangliosides in neurons
                                                           
The 3 Types of Tay-Sachs


  • Classical Tay-Sachs
Lipid build up begins during fetal development, but symptoms do not manifest until 3-6 months of age.

Symptoms include:

  • the stop of interactions with people
  • Starring gaze
  • Large head
  • Hyper-excitability to normal levels of noise
  • Weak / floppy muscles
  • No crawling or sitting
  • Complete blindness
  • Mental illness
  • Seizures at 1-2 years of age
  • Cherry spot on the retina


  • Juvenile hexosaminidase A deficiency
In this form of the disease, symptoms appear between the ages of 2-5. This disease is slower progressing, however, it results death around age 15.

Symptoms include:

  • Ataxia
  • Slurred speech
  • Muscle atrophy
  • Mental abilities, vision and hearing remain intact
  • Chronic hexosaminidase A deficiency (late onset)
In this form of the disease, symptoms appear between the ages of 5-30 and are milder than the infantile and juvenile forms.

Symptoms include:

  • Slurred speech
  • Difficulty walking due to weakness
  • Muscle cramps
  • Decreased coordination
  • Development of mental illness
  • Changes in intellect
  • Loss of hearing and vision
  • Great variation


History of Tay-Sachs

Tay Sachs was first documented by Warren Tay, MD, a British ophthalmologist, general surgeon, and dermatologist. In April 1881, a child of 12 months presented with a red spot on retina. Subsequent children from the same family had similar presentations. He noticed that the symptoms were specific enough that they must be attributed to an underlying disorder, with a genetic component. Shortly after in 1896, Bernard Sachs, MD, an American neurologist and psychiatrist (friends with Freud!) clinically described disease.


Who Is At Risk?

European and Russian (Ashkenazi) Jews are at high risk for developing Tay-Sachs. 1 in 27 in the US are carriers. 1 out of every 3,600 babies born to Ashkenazi Jewish couples have the disease. The Cajun population of of Louisiana also are at high risk for Tay-Sachs. 1 in 27 are carriers in the US. Irish Americans have a moderate risk, with 1 in 50 being carriers. French Canadians and the Pennslyvania Dutch are also mentionable ethnicities that are at higher risks for Tay-Sachs, whereas in the general population 1 in 250 people are carriers.


Diagnosis

An eye exam as well as a blood test can be used to obtain an affirmative diagnosis of Tay-Sachs. The eye exam looks for the cherry spot on the retina, while a blood test can be used to determine the quantity of Hex A in the blood. Skin cells and white blood cells can also be tested for Hex A quantity, because carriers will show half the normal amount of Hex A as a normal individuals and affected indiviuals will have no normal Hex A enzymes. DNA analysis is usually used for preventative measures, but can also be used as a diagnostic tool. The DNA analysis will show the mutation of the the HEX A gene on chromosome 15. Since the isolation of the HEX A gene in 1985, more than 50 mutations of this gene have been found to cause Tay-Sachs. For Ashkenazi Jews, specifically, the mutation is a substitution of serine for glycine at position 269 of the alpha subunit of beta-hexosaminidase.


Treatment

Currently there is no treatment or cure for Tay-Sachs disease, but there are some supportive treatments to prolong the lives of affected individuals, although the quality of life will not improve and they will still die eventually. These include anticonvulsant medicine, proper nutrition and hydration, keeping airways open and feeding tubes.


Prevention

Since there is no treatment currently, the best method to fight Tay-Sachs is to prevent it. This can be done by identifying Tay-Sachs carriers. Prior to conception, couples are given a DNA test, which will inform then about chances that they will have give birth to an affected child. If both parents are found to be carriers, then 50% of their offspring will also be carriers. Carriers appear healthy and function normally, although they only have half the amount of the normal Hex A enzyme, however, they run the risk of passing the mutated gene on to further generations. 25% of the offspring of 2 carriers will have Tay-Sachs, while 25% be will normal. If only one parent is a carrier then 50% of the offspring will also be carriers, but none of the offspring will have the disease.
In the Orthodox Jewish community, the organization Chevra Dor Yesharim Committee for Prevention of Jewish Genetic Diseases (Dor Yesharim) genetically tests young couples, often before their first date, to see if either is a carrier for Jewish genetic disorders, such as Tay-Sachs. If both members of the couple are found to be carriers, and therefore there is a chance that the birth of their children will have a genetic disorder, the organization advises them against marriage. This prevents having to deal with tough choices, such as abortion later on, if the couple were to get married.
Fetal genetic testing can also be performed after conception. This is done at 11 weeks, during the first trimester by Chorionic Villi Sampling (CVS). Fetuses can also be tested at 16 weeks, at the start of the second trimester using amniocentesis. If the baby is positive for Tay-Sachs, then the parents may choose to abort the fetus.
Reproductive therapy is another option for carrier couples. This method pre-screens eggs and sperm for the HEX A gene. Non carrier gametes are then selected and implanted using in-vitro fertilization.
Because of these preventative measures, the frequency of Tay-Sachs births has been low. In 2003, ten babies were born in North America with Tay-Sachs and 1 was born in Israel. In 2004, no Tay-Sachs babies were born in North America or Israel.


Prospective Treatments

Since there are no current treatments for any form of Tay-Sachs disease, ongoing research is being conducted to use new technology and advances in biomedical research to find a treatment.
  • Substrate Deprivation
The goal of substrate deprivation therapy is to decrease the amount of gangolosides GM2 is produced by the cells. This treatment only helps to prevent future build-up of gangliosides it does not repair any accumulation that has already occurred. This is a problem because in classical and junvielle tay-sachs buildup of gangliosides begins early in development. By the time the child is born and exhibiting symptoms to warrant the treatment, the treatment would not be effective. However, this treatment could be more effective in late onset Tay-Sachs disease since it is slower progressing. Another potential problem with substrate deprivation is that has only been seen to prolog life 40% in animal models even when administered in an early pre-symptomatic stage. This would not be a cure and the prognosis will still be death.
  • Chemical Chaperones
Chemical chaperones are small inhibitors that would help stabilize the abnormal hex A enzyme and allow it to be transported to the lysosome where it could help break down some of the accumulated gangliosides. This approach has the potential to help both classical and late onset forms of Tay-Sachs
  • Stem Cells
Currently, animal models for Tay-Sachs are being developed to explore transplating neural stem cells into the central nervous system. It is known that human neural stem cells have the ability to differentiate into different neural cell types. In addition, human neural stem cells can migrate throughout the mice brain after an intra-cerebral injection. This is important because this method of administration could provide a global source of hex A. Another form of stem cell research being explored is mesenchymal bone marrow cells. It would be easier to use these types of stem cells because they are more easily obtained than neural stem cells. The can be derived or transferred from the individual’s body that is in need of the treatment. This reduces the chance of rejection. Also, mesenchymal bone marrow cells have the ability to differentiate and migrate throughout the brain after an intra-cerebral injection just as neural stem cells can.
Another source of stem cells is umbilical cord blood. Martin, Carter, Kernan, Sahdev, Wall, Pietryga et al. (2006) investigated the use of stem cells in cord blood to treat lysosomal and peroxisomal storage diseases (LSDs) in 69 children (mean age = 1.8 years), 3 of which had Tay-Sachs disease. Patients were transplanted with the cord blood and monitored carefully under hospital supportive care. One-hundred and eighty days following transplantation, 80% of the participants survived, and there was a 72% survival rate after 1 year. After a 24.5 month follow up, 68% of the patients survived. For higher does of stem cells (above 1.5 x 10^7kg), the median white blood cell graft time was 22 days compared to 32.5 days for doses below this level. Engraftment was also successful in blood platelets, with 49 patients achieving engraftment of 20,000 μL and 42 subsequently achieved engraftment of 50,000 μL. Patients who did not respond well to the treatment contracted GVHD, infection or suffered toxicity. Survival improved with higher matches of antigens of the cord blood cells to the patient. Results suggest that stem cell transplantation is a viable method of prolonging life in LSD patients. Further research is needed to study the effects on the improvement of the quality of life in these children.


  • Olionucleotide Recombination
Olionucleotide recombination is being looked into as a possible treatment for Tay-Sachs disease, because a DNA strand can be designed to recombine with mutated DNA and replace the mutation with the normal sequence. If this can be accomplished, each cell will have the blue print to produce healthy, active Hex A enzymes that can break down future, and already existing gangolosides in the cell. This technique is limited, because researchers have yet to find a method of global delivery or a mechanism by which the cells can uptake the new DNA sequence without destroying it.


Ethical Concerns

There is much debate surrounding both prevention measures and prospective treatments for Tay-Sachs disease. Preventative measures, like genetic testing of married individuals in groups that are at high risk for being a carrier for Tay-Sachs, is potentially controversial. If trends in reproductive counseling continue, this may eventually lead to a depletion of individuals with disabilities from the population. In a more extreme sense, genetic counseling can decide who should be allowed to reproduce. Abortion is also a issue raised in Tay-Sachs disease. When is it ok to have an abortion? Should a fetus diagnosed with Tay-Sachs, which has a prognosis of certain death be born? Even the stem cell research being conducted to find a treatment for Tay-Sachs is swarming with ethical and religious concerns. Finally, the prospective treatments can prolong the life span of the patient, but do not necessarily improve their quality of life.


Helpful Links


Sources

  • Chicago Center for Jewish Genetic Disorders (2003). An Overview of Halakhic Issues
Pertaining to Jewish Genetic Disorders. Retrieved February 9, 2007 from
http://www.jewishgeneticscenter.org/rabbis/overview/
  • Cachon-Gonzlez, B., Wang, S., Ziegler, R., Cheng, S. H., & Cox, T. M. (2006). Effective gene
therapy in an authentic mouse model of tay-sachs related diseases. Molecular Therapy, 13, :226.
  • Densnick, R. J., & Kaback, M. M. (2001). Future perspectives for tay-sachs disease.
Advances in Genetics, 44, 349-356.
  • Fernandes, J. A., & Shapiro, B. E. (2004). Tay-sachs disease. Archives of Neurology, 61, 1466-1467.
  • Genetics Home Reference (2006, Aug). Tay-Sachs disease. Retrieved February 1, 2007 from
http://ghr.nlm.nih.gov/condition%3Dtaysachsdisease
  • Gale Encyclopedia of Medicine (1999). Tay-Sachs disease. Retrieved February 3, 2007 from
http://findarticles.com/p/articles/mi_g2601/is_0013/ai_2601001326
  • About:Judaism (2007). Tay-Sachs Disease. Retrieved February 9, 2007 from
http://judaism.about.com/od/health/p/taysachs.htm
  • Martin, L.P., Carter, S.L., Kernan, N.A., Sahdev, I., Wall, D., Pietryga, D., et al. (2006).
Results of the Cord Blood Transplanation Study (COBLT): Outcomes of Unrelated Donor Umbilical
Cord Blood Transplantation in Pediatric Patients with Lysosomal and Perxisomal Storage
Diseases. Biology of Blood and Marrow Transplantation 12, 184-194.
  • Medline Plus (2005, February 9). Tay-Sachs disease. Retrieved February 1, 2007 from
http://www.nlm.nih.gov/medlineplus/ency/article/001417.htm
  • National Human Genome Research Institute (2006, August). Learning About Tay-Sachs Disease.
Retrieved February 1, 2007 from http://www.genome.gov/10001220
  • National Institute of Neurological Disorders And Stroke (2007). Tay-Sachs Disease
Infromation Page. Retrieved January 30, 2007, from http://www.ninds.nih.gov
  • National Tay-Sachs & Allied Diseases Association, Inc. (2007) The Disease.
Retrieved January 30, 2007, from http://www.ntsad.org
  • Paw, B.H., Kaback, M.M., Neufeld, E.F. (1989). Molecular basis of adult-onset and chronic GM2
gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at
position 269 of the alpha-subunit of beta-hexosaminidase. Proc Natl Acad Sci USA, 86(7),
2413-2417.
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