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