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.
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