The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye in 1881, and the American neurologist Bernard Sachs of Mount Sinai Hospital, New York who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887.
Research in the late 20th century demonstrated that Tay-Sachs disease is caused by a genetic mutation on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in several populations. French Canadians of southeastern Quebec have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. Many Cajuns of southern Louisiana carry the same mutation that is most common in Ashkenazi Jews. Most HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.
Tay-Sachs disease is a rare disease. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common. The importance of Tay-Sachs lies in the fact that an inexpensive enzyme assay test was discovered and subsequently automated, providing one of the first "mass screening" tools in medical genetics.
Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms. The variant forms reflect diversity in the mutation base.
All patients with Tay-Sachs disease have a "cherry-red" spot, easily observable by a physician using an ophthalmoscope, in the back of their eyes (the retina). This red spot is the area of the retina which is accentuated because of gangliosides in the surrounding retinal ganglion cells (which are neurons of the central nervous system). The choroidal circulation is showing through "red" in this region of the fovea where all of the retinal ganglion cells are normally pushed aside to increase visual acuity. Thus, the cherry-red spot is the only normal part of the retina seen. Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides.
The development of improved testing methods has allowed neurologists to diagnose Tay-Sachs and other neurological diseases with greater precision. Until the 1970s and 80s, when the molecular genetics of the disease became known, the juvenile and adult forms of the disease were not recognized as variants of Tay-Sachs. Post-infantile Tay-Sachs was often mis-diagnosed as another neurological disorder, such as Friedreich ataxia.
The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexasaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When Hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and cause problems. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity. TSD is a recessive genetic disorder, meaning that both parents must be carriers in order to give birth to an affected child. Then, there is a 25% chance with each pregnancy of having a child with TSD. Prenatal monitoring of pregnancies is available.
Hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A, and the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific cofactor for the enzyme. Deficiency in any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells. Tay-Sachs disease (along with GM2-gangliosidosis and Sandhoff disease) occurs because a genetic mutation inherited from both parents deactivates or inhibits this process. Most Tay-Sachs mutations appear not to affect functional elements of the protein. Instead, they cause incorrect folding or assembly of the enzyme, so that intracellular transport is disabled.
The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. More than 90 mutations have been identified to date in the HEXA gene, and new mutations are still being reported. These mutations have included base pair insertions and deletions, splice site mutations, point mutations, and other more complex patterns. 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.
For example, a four base pair insertion in exon 11 (1278insTATC) results in an altered reading frame for the HEXA gene. This mutation is the most prevalent mutation in the Ashkenazi Jewish population, and leads to the infantile form of Tay-Sachs disease. The same mutation occurs in the Cajun population of southern Louisiana, an American ethnic group that has been isolated for several hundred years because of linguistic differences. Researchers have traced carriers from several Louisiana families to a single founder couple, not known to be Jewish, that lived in France in the 18th century.
An unrelated mutation, a long sequence deletion, occurs with similar frequency in families with French Canadian ancestry, and has the same pathological effects. Like the Ashkenazi Jewish population, the French Canadian population grew rapidly from a small founder group, and remained isolated from surrounding populations because of geographic, cultural, and language barriers. In the early days of Tay-Sachs research, the mutations in these two populations were believed to be identical. Some researchers claimed that a prolific Jewish ancestor must have introduced the mutation into the French Canadian population. This theory became known as the "Jewish Fur Trader Hypothesis" among researchers in population genetics. However, subsequent research has demonstrated that the two mutations are unrelated, and pedigree analysis has traced the French Canadian mutation to a founding family that lived in southern Quebec in the late 17th century.
In the 1960s and early 1970s, when the biochemical basis of Tay-Sachs disease was first becoming known, no mutations had been sequenced directly for any genetic diseases. Researchers of that era did not yet know how common polymorphism would prove to be. The "Jewish Fur Trader Hypothesis," with its implication that a single mutation must have spread from one population into another, reflected the knowledge of the time. Subsequent research has proven that a large number of HEXA mutations can cause some form of the disease. Because Tay-Sachs disease was one of the first genetic disorders for which widespread genetic screening was possible, it is one of the first genetic disorders in which the prevalence of compound heterozygosity was demonstrated.
Compound heterozygosity ultimately explains some of the variability of the disease, including late-onset forms. The disease can potentially result from the inheritance of two unrelated mutations in the HEXA gene, one from each parent. Classic infantile TSD results when a child has inherited mutations from both parents that completely inactivate the biodegradation of gangliosides. Late onset forms of the disease occur because of the diverse mutation base. Patients may technically be heterozygotes, but with two different HEXA mutations that both inactivate, alter, or inhibit enzyme activity in some way. When a patient has at least one copy of the HEXA gene that still enables some hexosaminidase A activity, a later onset form of the disease occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.
Genetic screening for carriers of Tay-Sachs disease is possible because an inexpensive enzyme assay test is available. It detects lower levels of the enzyme hexosaminidase A in serum. Developed and then automated during the 1970s, the enzyme assay test is not as precise as genetic testing based on polymerase chain reaction (PCR) techniques; however, it is cost effective for much broader use and allows screening for a disease that is rare in most populations. Couples with positive or ambiguous test results on the enzyme assay test may be referred for more precise screening. Current 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. PCR testing is more effective when the ancestry of both parents is known, allowing for proper selection of genetic markers. Genetic counselors, working with couples that plan to conceive a child, assess risk factors based on ancestry to determine which testing methods are appropriate. As the cost of PCR techniques declines and knowledge about mutations increases, it may become possible to screen for all mutations.
Proactive testing has been quite effective in eliminating Tay-Sachs occurrence among Ashkenazi Jews, both in Israel and in the diaspora. On January 18, 2005, the Israeli English language daily Haaretz reported that as a "Jewish disease" Tay-Sachs had almost been eradicated. Of the 10 babies born with Tay-Sachs in North America in 2003, none had been born to Jewish families. In Israel, only one child was born with Tay-Sachs in 2003, and preliminary results from early 2005 indicated that none were born with the disease in 2004.
Three general classes of theories have been proposed to explain the high frequency of Tay-Sachs carriers in the Ashkenazi Jewish population:
Because Tay-Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases. The researchers of the 1970s often favored theories of heterozygote advantage, but failed to find much evidence for them in human populations. They were also unaware of the diversity of the Tay-Sachs mutation base. In the 1970s, complete genomes had not yet been sequenced, and researchers were unaware of the extent of polymorphism. The contribution to evolution of genetic drift (as opposed to natural selection) was not fully appreciated.
Since the 1970s, DNA sequencing techniques using PCR have been applied to many genetic disorders, and in other human populations. Several broad genetic studies of the Ashkenazi population (not related to genetic disease) have demonstrated that the Ashkenazi Jews are the descendants of a small founder population, which may have gone through additional population bottlenecks. These studies also correlate well with historical information about Ashkenazi Jews. Thus, a preponderance of the recent studies have supported the founder effects theory.
Tay-Sachs disease has become a model for the prevention of all genetic diseases. In the United States before 1970, the disease affected about 50–70 infants each year in Ashkenazi Jewish families. About 10 cases occurred each year in infants from families without identifiable risk factors. Before 1970, the disease had never been diagnosed at the time of birth. Physicians saw the disease for the first time in infants that failed to thrive, and they could do nothing for the parents or family. Although the genetic basis of the disease was understood, antenatal testing was not available, and families with a Tay-Sachs infant faced a one in four probability of another devastating outcome with each future pregnancy.
Michael Kaback, a medical resident in pediatric neurology at Johns Hopkins University, saw two Tay-Sachs families in 1969. At the time, researchers had just uncovered the biochemical basis of the disease as the failure of an enzyme in a critical metabolic pathway. Kaback developed and later automated an enzyme assay test for detecting heterozygotes (carriers). This inexpensive test proved statistically reliable, with low rates of both errors and false positives. For the first time in medical history, it was possible to screen broadly for a genetic disease, and a physician or medical professional could counsel a family on strategies for prevention. Within a few decades, the disease had been virtually eliminated among Ashkenazi Jews. Most cases today are in families that do not have identifiable risk factors.
Kaback and his associates also developed the first mass screening program for genetic disease. Every aspect of this landmark study was meticulously planned, including community liaison, blood-draw procedure, laboratory set-up, assay protocol, and follow-up genetic counseling. On a Sunday in May 1971, more than 1800 young adults of Ashkenazi Jewish ancestry in the Baltimore and Washington D.C. area were voluntarily screened for carrier status. The success of the program demonstrated the efficacy of voluntary screening of an identifiable at-risk populations. Within a few years, these screening programs had been repeated among Ashkenazi Jews throughout the United States, Canada, western Europe, and Israel.
In the first 30 years of testing, from 1969 through 1998, more than 1.3 million persons were tested, and 48,864 carriers were identified. In at-risk families, among couples where both husband and wife were carriers, more than 3000 pregnancies were monitored by amniocentesis or chorionic villus sampling. Out of 604 monitored pregnancies where there was a prenatal diagnosis of Tay-Sachs disease, 583 pregnancies were terminated. Of the 21 pregnancies that were not terminated, 20 of the infants went on to develop classic infantile Tay-Sachs disease, and the 21st case progressed later to adult-onset Tay-Sachs disease. In more than 2500 pregnancies, at-risk families were assured that their children would not be affected by Tay-Sachs disease. Only three fetuses with infantile TSD were incorrectly diagnosed as being unaffected.