Prenatal Diagnosis of Tay-Sachs Disease

Tay-Sachs disease (TSD) is an autosomal recessive lysosomal storage disorder caused by mutations of the HEXA gene resulting in the deficiency of hexosaminidase A (Hex A) and subsequent neuronal accumulation of G_M2 gangliosides. Infantile TSD is a devastating and fetal neurodegenerative disease with death before the age of 3-5 years. A small proportion of TSD patients carry milder mutations and may present juvenile or adult onset milder disease. TSD is more prevalent among Ashkenazi Jewish (AJ) individuals and some other genetically isolated populations with carrier frequencies of approximately ~1:27 which is much higher than that of 1:300 in the general population. Carrier screening and prenatal testing for TSD are effective in preventing the birth of affected fetuses greatly diminishing the incidence of TSD. Testing of targeted HEXA mutations by genotyping or sequencing can detect 98% of carriers in AJ individuals; however, the detection rate is much lower for most other ethnic groups. When combined with enzyme analysis, above 98% of carriers can be reliably identified regardless of ethnic background. Multiplex PCR followed by allele-specific primer extension is one method to test for known and common mutations. Sanger sequencing or other sequencing methods are useful to identify private mutations. For prenatal testing, only predefined parental mutations need to be tested. In the event of unknown mutational status or the presence of variants of unknown significance (VUS), enzyme analysis must be performed in conjunction with DNA-based assays to enhance the diagnostic accuracy. Enzymatic assays involve the use of synthetic substrates 4-methylumbelliferyl-N-acetyl-β-glucosamine (4-MUG) and 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside (4-MUGS) to measure the percentage Hex A activity (Hex A%) and specific Hex A activity respectively. These biochemical and molecular tests can be performed in both direct specimens and cultured cells from chorionic villi sampling or amniocentesis.