Tay-Sachs disease: Screening and counseling families at risk for metabolic disease

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Goals

This article will discuss carrier screening and prenatal testing for Tay-Sachs disease. At the completion of the article the reader should be able to discern:

  • Who should be offered carrier testing

  • What testing methods to use

  • How to interpret lab results

  • How to counsel couples at risk

Disease

Tay-Sachs disease is an autosomal recessive, neurodegenerative disorder that results from excess storage of the cell membrane glycolipid, GM2 ganglioside, within the lysosomes of cells. Tay-Sachs disease is characterized by normal motor development in the first few months of life, followed by progressive weakness and loss of motor skills beginning around 2 to 6 months of age. This is followed by decreased social interaction and an increased startle response. Physical examination reveals

Who to test

In accordance with guidelines from the American College of Obstetrics and Gynecology and the American College of Medical Genetics, carrier testing for Tay-Sachs disease should be offered to individuals whose ancestry is fully or partially Jewish [17]. As well, other groups with a high frequency of Tay-Sachs carriers should be offered testing, including Pennsylvania Dutch, Cajuns of Southern Louisiana, and French Canadians of Eastern Quebec. Because Tay-Sachs is an autosomal recessive disease,

Enzyme assay

Enzyme assay for diagnosis of Tay-Sachs disease and carrier status is a fluorimetric study that measures activity of both Hex A and Hex B in either serum or leukocytes. Carriers of Tay-Sachs disease have decreased activity of Hex A with normal or increased activity of Hex B. The reaction uses an artificial substrate (typically a 4-methylumbelliferyl glucosamine) that permits fluorimetric detection of the hydrolyzed product. The advantage of the Hex A and Hex B assay in serum is that the assay

Interpreting results

Testing of both Ashkenazi Jewish individuals and non-Jews for Tay-Sachs carrier status may utilize enzyme analysis, DNA diagnostics, or both studies in combination. Two percent of Ashkenazi Jews and 35% of non-Jews who have enzyme analysis results in the carrier range will carry pseudodeficiency alleles and not disease causing mutations. As well, DNA testing can confirm carrier status, and identification of the disease causing mutation can permit accurate prenatal diagnosis. Thus, all

Summary

Carrier testing for Tay-Sachs disease should be offered to couples when at least one individual is of Ashkenazi Jewish (carrier frequency 1/30), Pennsylvania Dutch, Southern Louisiana Cajun, or Eastern Quebec French Canadian descent. Ideally, testing is done prior to conception. For Ashkenazi Jews, in whom DNA testing identifies 99.9% of carriers, DNA testing is the preferred method to ascertain carriers [14]. For non-Jewish individuals seeking carrier testing, enzyme assay should be done

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