ICD-10 | E75.0 |
---|---|
ICD-9 | 330.1 |
OMIM | 272800 272750 |
DiseasesDB | 12916 |
MedlinePlus | 001417 |
eMedicine | ped/3016 |
Tay-Sachs disease (abbreviated TSD, also known as "GM2 gangliosidosis") is a genetic disorder, fatal in its most common variant known as Infantile Tay-Sachs disease. TSD is inherited in an autosomal recessive pattern. The disease occurs when harmful quantities of a fatty acid derivative called a ganglioside accumulate in the nerve cells of the brain. Gangliosides are present in lipids, which are components of cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs disease, is especially common in the nervous tissue of the brain.
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 who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887. It has been suggested that asymptomatic carriers of Tay-Sachs (those with one defective version of HEXA and one normal gene) may have a selective advantage, but this has never been proven.
Research in the late 20th century demonstrated that Tay-Sachs disease is caused by mutations 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 and Cajuns of southern Louisiana have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. 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.
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Tay-Sachs is classified in variant forms, based on the time of onset of neurological symptoms.[1] The variant forms reflect diversity in the mutation base.
All patients with Tay-Sachs 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 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 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 Hexasaminidase 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. Even then, there is only 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 inactivates 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. [5]
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 alter the protein product, and thus inhibit 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.[6] The same mutation occurs in the Cajun population of southern Louisana, an American ethnic group that has been isolated for several hundred years because of linguistic differences. Researchers have speculated that it may have entered this population because a Jewish merchant family assimilated into Cajun society.
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.[7]
Tay-Sachs 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.
Screening for Tay-Sachs disease was one of the first great successes of the emerging field of genetic counseling and diagnosis. Jewish communities, both inside and outside of Israel, embraced the cause of genetic screening from the 1970s on. Success with Tay-Sachs disease lead Israel to become the first country to offer free genetic screening and counseling for all couples. Israel has become a leading center for research on genetic disease. Both the Jewish and Arab/Palestinian populations in Israel contain many ethnic and religious minority groups, and Israel's initial success with Tay-Sachs disease has lead to the development of screening programs for other diseases.
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 during the 1970s, the enzyme assay test is not as accurate 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. 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.
Proactive testing has been quite effective in eliminating Tays-Sachs occurrence amongst Ashkenazi Jews. Of the 10 babies born with Tay-Sachs in North America in 2003, none were 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 approaches have been used to prevent or reduce the incidence of Tay-Sachs disease in the Ashkenazi Jewish population:
There is currently no cure or treatment for TSD. Even with the best care, children with Infantile TSD die by the age of 4[11], and the progress of Late-Onset TSD can only be slowed, not treated.
Historically, Eastern European people of Jewish descent (Ashkenazi Jews) have a high incidence of Tay-Sachs and other lipid storage diseases. Documentation of Tay-Sachs in this Jewish population reaches back to 15th century Europe. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of a person being a carrier. In the general population, the incidence of carriers (heterozygotes) is about 1 in 300. [12]
A continuing controversy is whether heterozygotes, individuals who are carriers of one copy of the gene but do not actually develop the disease, have some selective advantage. The classic case of heterozygote advantage is sickle cell anemia, and some researchers have argued that there must be some evolutionary benefit to being a heterozygote for Tay-Sachs as well. Four different 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 preponderence of the recent studies have supported the founder effects theory.[16][17][18]