Tay-Sachs Disease

 

BACKGROUND:

Tay-Sachs disease, the classic infantile variant of GM2 gangliosidosis, results from mutations in the hexosaminidase A gene, inherited in an autosomal recessive manner. Accumulation of undegraded GM2 gangliosides in the lysosomes of affected individuals results in progressive neurodegeneration. Clinical features include onset at 3-5 months developmental arrest, hyperacusis and macular cherry red spots followed by blindness, intractable seizures and neurological deterioration leading to death at 3-5 years. The disease occurs at particularly high frequency in Ashkenazi Jewish populations with a carrier frequency of 1:31 (carrier frequency in non-Jewish groups is ~1:300).

INDICATIONS FOR TESTING:

  • Family history of Tay-Sachs disease.

  • Prenatal diagnosis for at risk couples.

  • Ashkenazi Jewish Ancestry

  • Individuals determined to be carriers or affected with Tay-Sachs by standard biochemical testing.

INTERPRETATION:

PCR based assays detect three mutations (+TATC 1278, +1 IVS 12, G269S) that account for 95% of disease mutations in Ashkenazi Jews, as well as two mutations (A247T and A249T) that constitute pseudodeficiency alleles. Report includes background information, analysis of assay results and estimation of residual carrier risk if mutation results are negative.

COUNSELING ISSUES:

  1. Two pseudodeficiency mutations that are clinically benign (A247T and A249T) but not differentiated by standard biochemical testing represent 3% of Ashkenazi Jewish alleles and 36% of non Jewish mutations. Therefore, a carrier or affected diagnosis established by enzyme activity should be confirmed by mutation analysis.

  2. Since mutation frequency varies markedly among different populations, inaccurate information regarding ethnicity can confound calculation of residual carrier risk for individuals with negative test results.

  3. Reliable information regarding Ashkenazi ancestry is important for accurate residual carrier determination when mutations are not detected.

SPECIAL NOTE:

Analysis for this disorder can be accomplished by both biochemical and molecular methods (see biochemical section). The use of these different technologies is complementary. The decision as to which tests are appropriate for any sample is made on a case by case basis. For further information on handling of any sample, please contact the Center.

 

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