Dr. Warren Tay (1843-1927) and Dr. Bernard Sachs (1858-1944) were the two men for which Tay-Sachs disease was named. (U.S. National Library of Medicine 2010). In 1881, Dr. Warren Tay was an ophthalmologist from Britain who first identified a patient with a cherry-red spot on the retina of their eye (Mayo Clinic 2010). A neurologist from New York, Bernard Sachs, worked a few years later and gave the first report on the cellular basis of Tay-Sachs disease. Sachs also realized that the disorder was familial (U.S. National Library of Medicine 2010).
http://www.utm.utoronto.ca/~w3bio315/picts/lectures/lecture15/LysosomeTaySachs1.jpgTay 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 (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.
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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 have included base pair insertions and deletions, splice site mutations, point mutations, and other more complex patterns (Mayo Clinic 2010). Each of these mutations alters the protein product, and thus inhibits the function of the enzyme in some manner. In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations such as the documented cases of 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). By the time a child with Tay-Sachs disease is three or four years old, the nervous system is so badly affected that life itself cannot be supported (Mayo Clinic 2010). Even with the best of care, all children with classical Tay-Sachs disease will die early in childhood, usually by the age of five (Mayo Clinic 2010).
A baby with Tay-Sachs disease appears normal at birth and seems to develop normally until about six months of age (Office of Communications 2007). The first signs of Tay-Sachs can vary and are evident at different ages in affected children. Initially, development slows, there is a loss of peripheral vision, and the child exhibits an abnormal startle response (Mayo Clinic 2010).
By about two years of age, most children experience recurrent seizures and diminishing mental function. The infant gradually regresses, losing skills one by one, and is eventually unable to crawl, turn over, sit, or reach out (Office of Communications 2007). Other symptoms include increasing loss of coordination, progressive inability to swallow and breathing difficulties. Eventually, the child becomes blind, mentally retarded, paralyzed, and non-responsive to his or her environment (Mayo Clinic 2010).
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There are actually three variant forms of Tay-Sachs disease. The first and most common is the infantile form. This is characterized by Infants with Tay-Sachs disease appearing to develop normally for the first six months of life. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of 4 (Office of Communications 2007).
Juvenile Tay-Sachs is extremely rare, and usually presents itself in children between 2 and 10 years of age (Mayo Clinic 2010). They develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile Tay-Sachs usually die between 5-15 years (Office of Communications 2007).
Adult/Late Onset Tay-Sachs is a rare form of the disorder that generally occurs in patients in their 20s and early 30s. LOTS (Late Onset Tay-Sachs Disease) is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis (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 techniques for testing for the Tay-Sachs mutations. The first is enzyme assay that tests the phenotype at a molecular level and tests for the presence of specific enzyme activity such as that of hexosaminidase A (Park et al. 2010). The second method is mutation analysis that tests the genotype for mutations directly. These two tests are usually both conducted together so as to receive a definitive result (Mayo Clinic 2010). Enzyme assay techniques detect individuals with lower levels of hexosaminidase A (Park et al. 2010).
Development of a serum enzyme assay test made it feasible to conduct large scale screening for Tay-Sachs in targeted at-risk populations (Tropak 2009). Developed in the late 1960s and then automated during the 1970s, the serum test was a first in medical genetics (Park et al. 2010). It produced few false positives among the first group targeted for screening. Because serum can be drawn at low cost and without an invasive procedure, it is the preferred tissue for enzyme assay testing (Park et al. 2010). Whole blood is normally drawn, but the enzyme assay measures activity in leukocytes, white blood cells that represent only a small fraction of whole blood. However, serum testing gives inconclusive results in about 10% of cases when used to screen individuals from the general population (Park et al. 2010).
Although early testing for human mutations was often conducted by extracting DNA from larger tissue samples, modern testing in human subjects generally employs polymerase chain reaction because small tissue samples can be obtained by minimally invasive techniques, and at very low cost (Mayo Clinic 2010). PCR techniques amplify a sample of DNA and then test genetic markers to identify actual mutations. Current PCR testing methods screen a panel of the most common mutations, although this leaves open a small probability of both false positive and false negative results (Park et al. 2010). PCR testing is more effective when the ancestry of both parents is known, allowing for proper selection of genetic markers (Mayo Clinic 2010). Genetic counselors, working with couples that plan to conceive a child, assess risk factors based on ancestry to determine which testing methods are appropriate (Park et al. 2010).
In addition to prevention through screening, other methods to reducing incidence have been devised. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective copy of the gene from both parents (Delatycki 2008). For couples who are willing to terminate the pregnancy, this eliminates the risk of Tay-Sachs, but abortion raises ethical issues for many families (Delatycki 2008).
Chorionic villus sampling (CVS), which can be performed after the 10th week of gestation, is the most common form of prenatal diagnosis (Park et al. 2010). Both CVS and amniocentesis present developmental risks to the fetus that need to be balanced with the possible benefits, especially in cases where the carrier status of only one parent is known (Office of Communications 2007).
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Also, by retrieving the mother's eggs for in vitro fertilization and conceiving a child outside the womb, it is possible to test the embryo prior to implantation (Park et al. 2010). Only healthy embryos are selected for transfer into the mother's womb (Kaback 1999). In addition to Tay-Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis, sickle cell anemia, Huntington's disease, and other genetic disorders. However this method is expensive. It requires invasive medical technologies, and is beyond the financial means of many couples (Park et al. 2010).
Since Tay-Sachs disease is a lysosomal storage disorder, the research strategies have been those for lysosomal storage disorders in general (Mayo Clinic 2010). Several methods of treatment have been investigated for Tay-Sachs disease, but none have passed the experimental stage (Park et al. 2010).
Several enzyme replacement techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat Tay-Sachs disease. The goal would be to replace the missing enzyme, a process similar to insulin injections for diabetes. However, the HEXA enzyme has proven to be too large to pass through the blood into the brain through the blood-brain barrier (Park et al. 2010). Blood vessels in the brain develop junctions so small that many toxic (or large) molecules cannot enter into nerve cells and cause damage (Kaback 1999). Researchers have also tried instilling the enzyme into cerebrospinal fluid, which bathes the brain. However, neurons are unable to take up the large enzyme efficiently even when it is placed next to the cell, so the treatment is still ineffective(Park et al. 2010).
Several options for gene therapy have been also been explored for Tay-Sachs and other lysosomal storage diseases (Mayo Clinic 2010). If the defective genes could be replaced throughout the brain, Tay-Sachs could theoretically be cured (Kaback 1999). However, researchers working in this field believe that they are years away from the technology to transport the genes into neurons, which would be as difficult as transporting the enzyme (Park et al. 2010). Use of a viral vector, promoting an infection as a means to introduce new genetic material into cells, has been proposed as a technique for genetic diseases in general. Hematopoetic stem cell therapy (HSCT), another form of gene therapy, uses cells that have not yet differentiated and taken on specialized functions. Yet another approach to gene therapy uses stem cells from umbilical cord blood in an effort to replace the defective gene (Kaback 1999). Although the stem cell approach has been effective with Krabbé disease, no results for this method have been reported with Tay-Sachs disease (Park et al. 2010).
Other highly experimental methods being researched involve manipulating the brain's metabolism of GM2 gangliosides. One experiment has demonstrated that, by using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides can be metabolized so that they become almost inconsequential (Cornfield 2008).
If a safe pharmacological treatment can be developed, one that causes the increased expression of lysosomal sialidase in neurons, a new form of therapy, essentially curing the disease, could be on the horizon.