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Tay Sachs is an autosomal recessive disorder (Mayo Clinic 2010). Autosomal recessive disorders affect the carriers when a person possesses two recessive (or in this case defective) copies of an autosomal gene. Neither copy of this gene can be transcribed or expressed as a functional enzyme (Broomkamp et al. 2010). Insufficient activity of the enzyme called hexosaminidase A is what causes Tay-Sachs disease (Bean et al. 2009). This enzyme catalyzes the breakdown of fatty acid derivatives known as gangliosides. Hexosaminidase A is a key hydrolytic enzyme that breaks down lipids and is found in lysosomes (Cornfield 2008). When Hexosaminidase A does not function properly, lipids gather in the brain and then they interfere with the brain's biological processes (Broomkamp et al. 2010). Gangliosides are produced and broken down very quickly in early childhood as the brain develops (Cornfield 2008). Both sufferers and carriers of Tay-Sachs disease can be screened through the use of tests that accurately monitor hexosaminidase A activity.
Three proteins are needed for the hydrolysis of GM2-ganglioside (Bean et al. 2009). Two of these proteins needed are subunits of the enzyme hexosaminidase A. The third protein needed is a glycolipid transport protein called GM2 activator protein (GM2A). This protein acts as a substrate specific cofactor (Cornfield 2008). Storage of the ganglioside is brought on by a deficiency in any one of these proteins, mainly within the lysosomes of neurons (Broomkamp et al. 2010). Tay-Sachs disease therefore occurs because of a genetic mutation that deactivates or hinders this hydrolysis (Cornfield 2008). Most Tay-Sachs mutations seem to not affect the formation of the enzyme (Giraud et al. 2010). What does occur, however, is incorrect folding or assembly of the protein so transport within the cell is disabled (Bean et al. 2009).
As stated, Tay-Sachs disease is caused by mutations on the 15th chromosome in the Hex-A gene that codes for the alpha-subunit of the enzyme beta-N-acetylhexosaminidase A within a lysosome (Bean et al. 2009). In 2000, there was believed to be more than 100 mutations that had been linked to the HEXA gene and new mutations are still being reported even today (Kaback 1999). The mutations so far discovered have ranged from base pair insertions and deletions, splice site mutations, and point mutations to other more sophisticated mutation patterns (Mayo Clinic 2010). Each one of these mutations will somehow alter the enzymatic product. This will then inhibits the function of the functional protein. It has been learned recently in population studies and pedigree analysis that many mutations stem from several founder populations such as Ashkenazi Jews, Cajuns, and French Canadians (Mayo Clinic 2010).
The fatal process of Tay-Sachs begins for the fetus in early pregnancy, however it is not until the child is several months old that the disease becomes apparent (Office of Communications 2007). When a child with Tay-Sachs reaches the age of three to four the nervous system is so negatively affected that life can no longer persist (Mayo Clinic 2010). Even if provided with the top medical care, all children with the traditional form of Tay-Sachs disease will eventually die from it, and usually by sometime around the age of five (Mayo Clinic 2010).
At birth, a baby who is affected by Tay-Sachs disease visually appears normal and also appears to develop as a normal child until approximately 6 months of age (Office of Communications 2007). The initial symptoms of Tay-Sachs can vary and are usually more obvious at different ages in children. Primarily in children affected, development slows, peripheral vision is decreased, and the child expresses an abnormal response to startling (Mayo Clinic 2010).
By approximately the age of two, most children affected will experience recurrent seizures and will have decreased mental function. The symptoms of the disease will slowly worsen and cause the child to lose skills one by one. Eventually, the infant will unable to turn over, reach out, sit, or crawl (Office of Communications 2007). Some other symptoms also include an increasing loss of coordination, a slow worsening of the ability to swallow and difficulties with breathing. Soon the child becomes paralyzed, blind, mentally retarded, and non-responsive to their own environment (Mayo Clinic 2010).
There are actually three different forms of Tay-Sachs disease. The first and most common form of the disease is the infantile form. This variant is characterized by onset in infancy and the appearance to develop normally for nearly six months after birth. Slowly as nerve cells become encumbered with gangliosides, mental and physical abilities begin to deteriorate. The affected child may eventually become blind, deaf, and unable to swallow. Muscles will begin to atrophy and weaken and paralysis will also eventually prevail. Death usually occurs before the age of 4 (Office of Communications 2007).
Juvenile Tay-Sachs is a very rare variant of the disease. This variant usually presents itself in adolescents between the ages of 2 and 10 (Mayo Clinic 2010). The children will develop speech, cognitive, and motor difficulties, will have difficulty swallowing, and develop an unsteadiness of gait. Those affected with Juvenile Tay-Sachs usually die 5-15 years after the original onset (Office of Communications 2007).
Adult/Late Onset Tay-Sachs (LOTS) is an extremely rare variant of Tay-Sachs that usually occurs in by the age of 20 to 30. LOTS is very often misdiagnosed but is thankfully non-fatal. It is usually marked by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS are very similar to that of other variants of Tay-Sachs. These symptoms can include speech difficulty, spasticity, swallowing difficulties, cognitive decline, unsteadiness of gait, and even psychiatric illness (Mayo Clinic 2010).
While there is no cure or treatment for Tay-Sachs disease currently, the best way to treat the disease is by prevention so that it does not occur in the first place. For this reason, the main method of "treatment" is through preventative methods (Delatycki 2008). Currently there are two primary techniques for testing for the Tay-Sachs mutations. The first method is an enzyme assay that tests the phenotype at a molecular level. This assay tests for the presence of specific enzyme activity such as that of hexosaminidase A (Park et al. 2010). Enzyme assay techniques detect individuals with lower levels of hexosaminidase A activity (Park et al. 2010). The second method is through the use of mutation analysis that tests the genotype for mutations directly. Both of these tests are usually conducted simultaneously so as to receive a definitive diagnosis (Mayo Clinic 2010).
Serum enzyme assay tests make it possible to screen on a large scale for Tay-Sachs in a specific at-risk populations (Tropak 2009). The serum test was a first of its kind in medical genetics and was developed in the late 1960's and was then automated in the 1970's (Park et al. 2010). The test produced very few false positive test results among the initial people targeted for screening. Since serum is cheap to obtain and requires non-invasive techniques, it is the preferred medium for enzyme assay testing (Park et al. 2010). Whole blood can be drawn, but since the assay only measures activity within leukocytes, this is not accurate since white blood cells are only a small percentage of the blood. On the contrary, serum testing gives unclear results in only 10 percent of cases (Park et al. 2010).
While initial testing for mutations was originally done by extracting DNA from larger samples of tissue, more modern testing employs polymerase chain reaction since small tissue samples can be obtained and utilized through the use of minimally invasive techniques and very cheaply (Mayo Clinic 2010). PCR has the ability to amplify a sample of DNA and then identify mutations through the use of genetic markers. PCR testing methods usually scan for the most common mutations, although this can leave a small possibility of either false positive or negative results (Park et al. 2010). PCR testing can be more effective when the ancestry of both parents is known. This allows for proper selection of genetic markers for patients (Mayo Clinic 2010). Genetic counselors who often work with couples that are planning for a child can assess risk factors based on the client's ancestry in order to determine which testing method should work the best (Park et al. 2010).
In addition to prevention through screening, other methods to reducing incidence have been devised. If both parents have been identified as potential carriers, prenatal genetic testing can help to determine whether the fetus has received the defective copy of the gene from both parents (Delatycki 2008). For couples who are willing to deal with the controversy of abortion can terminate the pregnancy, and thus eliminates the risk of Tay-Sachs. This can obviously however raise ethical issues for many families (Delatycki 2008).
Chorionic villus sampling (CVS), can be performed after the 10th week of pregnancy. This is the most common form of prenatal diagnosis of many diseases (Park et al. 2010). CVS and amniocentesis can, however, increase developmental risks and this needs to be considered with the possible benefits of the procedures. This is especially the case when the carrier status of only one of the parents is known (Office of Communications 2007).
Also, by extracting eggs for in vitro fertilization and then conceiving a child outside the womb, it is possible to test embryos for potential defects prior to implantation (Park et al. 2010). Only the healthiest embryos would be selected for implantation within the mother's womb (Kaback 1999). In addition to Tay-Sachs disease, preimplantation genetic diagnosis has been used to prevent complications such as cystic fibrosis, sickle cell anemia, Huntington's disease, and other genetic disorders. The down side to this method of prevention is obviously that it is very expensive. It also employs invasive techniques and is well out of the price range of many couples (Park et al. 2010).
Since Tay-Sachs disease is a lysosomal storage disorder, many research strategies have been targeted toward treatment for lysosomal storage disorders on the whole (Mayo Clinic 2010). Numerous treatment methods have been investigated by researchers for Tay-Sachs disease, but none have yet to pass the experimental stage (Park et al. 2010).
A few enzyme replacement techniques have been investigated for lysosomal storage disorders. These techniques could become potential treatments for Tay-Sachs disease. The objective would be to replace the nonfunctioning enzyme in a process similar to that of insulin treatments for diabetes patients. Unfortunately, the HEXA enzyme has been shown to be far too large to pass through the blood-brain barrier (Park et al. 2010). Blood vessels in the brain are able to develop seals so that many small toxic molecules cannot enter the central nerve cells of the brain and cause damage (Kaback 1999). Researchers have also attempted to place the enzyme within cerebrospinal fluid. The neurons are not able engulf the large enzyme efficiently even when placed adjacent to the cell. This treatment, therefore has also proven to be ineffective (Park et al. 2010).
A few options for gene therapy have been also been analyzed for Tay-Sachs and other lysosomal storage disorders (Mayo Clinic 2010). Theoretically, if genetic mutations could be fixed throughout the brain, Tay-Sachs could be cured (Kaback 1999). However, current technology is far away from transporting new genes into a neuron. (Park et al. 2010). It has been proposed that a virus could be used as a vehicle for transference of the gene into the target cell.
Hematopoetic stem cell therapy (HSCT) is another form of gene therapy that may hold a cure. This process utilized cells that have not differentiated and adopted a specific cellular function. A similar technique proposed uses the stem cells that are naturally found in umbilical cord blood to replace the mutations within the gene (Kaback 1999). While stem cells have been successful in treating Krabbé disease, results for this method have yet to be reported with Tay-Sachs disease (Park et al. 2010).
Tay-Sachs is a tragic disorder that only kills approximately 100 infants in the U.S. yearly. It is, however, a disease that is 100% fatal. Developing treatment for the disease can give researchers insight into finding cures for many other similar genetic neurological diseases. If a safe pharmacological treatment can be developed, then a new form of therapy essentially curing the disease may be in the future.