Tay-Sachs Disease

What is Tay-Sachs Disease?

Tay-Sachs disease (abbreviated TSD, also known as GM2 gangliosidosis or Hexosaminidase A deficiency) is an autosomal recessive genetic disorder. In its most common variant known as infantile Tay-Sachs disease it presents with a relentless deterioration of mental and physical abilities which commences at 6 months of age and usually results in death by the age of four.

It is caused by a genetic defect in a single gene with one defective copy of that gene inherited from each parent. The disease occurs when harmful quantities of gangliosides accumulate in the nerve cells of the brain, eventually leading to the premature death of those cells. There is currently no cure or treatment. Tay-Sachs disease is a rare disease. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common.

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 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.

TSD is an autosomal recessive genetic disorder, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child.

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Tay-Sachs Disease Pathophysiology

The disease results from mutations on chromosome 15 in the ''HEXA'' gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. By the year 2000, more than 100 mutations had been identified 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. Initial research focused on several such founder populations:

  • Ashkenazi Jews. 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.
  • Cajun. The same mutation found among Ashkenazi Jews 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.
  • French Canadians. A mutation that is unrelated to the predominant Ashkenazi 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, it was believed that mutations in these two populations were identical, that gene flow accounted for the prevalence of TSD in eastern Quebec. 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.

Heterozygous carriers, individuals who inherit one mutant allele, show abnormal enzyme activity, but have no symptoms of the disease. Bruce Korf explains why carriers of recessive mutations generally do not manifest the symptoms of genetic disease: "The biochemical basis for the dominance of wild-type alleles over mutant alleles in inborn errors of metabolism can be understood by considering how enzymes function. Enzymes are proteins that catalyze chemical reactions, so only small quantities are required for a reaction to be carried out. In a person homozygous for a mutation in the gene encoding an enzyme, little or no enzyme activity is present, so he or she will manifest the abnormal phenotype. A heterozygous individual expresses at least 50% of the normal level of enzyme activity due to expression of the wild-type allele. This is usually sufficient to prevent phenotypic expression."

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Tay-Sachs Disease Diagnosis

Development of improved testing methods has allowed neurologists to diagnose Tay-Sachs and other neurological diseases with greater precision. But Tay-Sachs disease is sometimes misdiagnosed at first, because clinicians are not aware that it is not exclusively a Jewish disease.

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).


Screening for TSD is carried out with two possible objectives:

  • Carrier testing seeks to detect whether an individual unaffected by the disease is carrying one copy of a mutation. Many individuals seeking carrier screening are couples from at-risk populations who are seeking to start a family. Some individuals and couples who seek carrier screening are aware of test results or genetic disease in ancestors or living family members.
  • Prenatal testing seeks to determine whether the fetus has inherited two defective copies, one from each parent. In prenatal testing, there is generally greater information about family history and the mutations are often known precisely. Prenatal testing for TSD is usually undertaken when both parents cannot be ruled out as possible carriers. In some cases, the mother's carrier status may be known, while the father is unknown or unavailable for testing. Prenatal testing can be performed by assay of HEX A enzyme activity in fetal cells obtained by chorionic villus sampling or amniocentesis. If an actual mutation has been identified in both parents, then more precise mutational analysis techniques using PCR are available.

Two technical approaches to testing for Tay-Sachs mutations are available. The enzyme assay approach tests the phenotype at the molecular level by measuring levels of enzyme activity, while the mutation analysis approach tests the genotype directly, seeking known genetic markers. As with all biomedical tests, both approaches produce some false positive and false negative results. The two methods are used in tandem because an enzyme assay can detect all mutations with some inconclusive results, while mutation analysis can give definite results, but only for known mutations. Family history can be used to select a more effective testing protocol.

Both carrier and prenatal testing using enzyme assay became available in the 1970s. Mutation analysis was added to testing protocols gradually after 1990 as the costs of PCR techniques declined. Over time, as knowledge of the mutation base has increased, mutation analysis has played an increasingly significant role.

Enzyme assay techniques

Enzyme assay techniques detect individuals with lower levels of hexosaminidase A. Development of a serum enzyme assay test made it feasible to conduct large scale screening for Tay-Sachs in targeted at-risk populations such as Ashkenazi Jews. Developed in the late 1960s and then automated during the 1970s, the serum test was a first in medical genetics. It produced few false positives among Ashkenai Jews, the first group targeted for screening.

In enzyme assay, success with one targeted population cannot always be generalized to other populations, because the mutation base is diverse. Different mutations have different effects on enzyme assay results. Many polymorphisms are neutral, while others affect the phenotype without causing disease. Enzyme assay was particularly effective among Ashkenazi Jews because fewer pseudodeficiency alleles are found in this population, as compared with the general population.

Because serum can be drawn at low cost and without an invasive procedure, it is the preferred tissue for enzyme assay testing. 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. Serum testing gives inconclusive results in about 10% of cases when used to screen individuals from the general population. Serum testing also cannot be used to test pregnant women or women using hormonal birth control pills. To address these deficiencies, other techniques using enzyme assay have been developed.

Mutation analysis techniques

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. 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. 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.

Screening success with Ashkenazi Jews

Screening for Tay-Sachs carriers was one of the first great successes of the emerging field of genetic counseling and diagnosis. Proactive testing has been quite effective in eliminating Tay-Sachs occurrence among Ashkenazi Jews, both in Israel and in the diaspora. In the year 2000, Michael Kaback reported that in the United States and Canada, the incidence of TSD in the Jewish population had declined by more than 90% since the advent of genetic screening.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Tay-Sachs disease" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.