Clinical Information

Tay-Sachs disease is caused by an absence of hexosaminidase (Hex A) enzyme activity, which results in the accumulation of the sphingolipid GM2 ganglioside. Mutations within the alpha subunit of the hexosaminidase A gene, HEXA, cause the clinical manifestations associated with Tay-Sachs disease (TSD). The classic form of TSD becomes apparent in infancy when mild motor weakness is noted along with impaired visual acuity and the presence of a "startle response." Other manifestations of this condition include progressive neurodegeneration, seizures, and blindness leading to total incapacitation and death. Other types of TSD (eg, subacute and adult onset) are characterized by later ages of onset and death. The symptoms and severity of disease vary widely.

TSD is inherited in an autosomal recessive manner. The carrier frequency for TSD disease in the Ashkenazi Jewish population is 1/31. This panel tests for the 3 common mutations in the Ashkenazi Jewish population: 1278insTATC, G269S, and IVS12+1G->C. When performed in conjunction with hexosaminidase A biochemical testing, the mutation detection rate using this assay is approximately 99%. Also included in this analysis are the mutations IVS9+1G->A and 7.6 kb, del 5'UTR-IVS+1 that are over-represented in individuals of Celtic or French Canadian ancestry, respectively.

A common cause of false-positive carrier screening by enzyme analysis, particularly among individuals of non-Ashkenazi Jewish descent, is due to the presence of a pseudodeficiency allele, either R247W or R249W. These sequence variations are not associated with disease, but result in the production of a hexosaminidase A enzyme with decreased activity towards the artificial substrate used in the enzyme assay. Both pseudodeficiency alleles are evaluated for by this panel.

The recommended first-tier test to screen for TSD is biochemical analysis measuring hexosaminidase enzyme activity, NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes. Molecular tests form the basis of confirmatory diagnostic or carrier testing. See Tay-Sachs Disease Carrier Testing Protocol in Special Instructions for additional information.

Alternatively, full gene sequencing is available to evaluate for mutations in all coding regions and exon/intron boundaries of the HEXA gene by ordering HEXAZ / Tay-Sachs Disease, HEXA Gene, Full Gene Analysis.