Interpretive Handbook

Test 82588 :
Tay-Sachs Disease, Mutation Analysis, HEXA

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 kbdel 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. Refer to Carrier Testing for Tay-Sachs Disease and Other GM2 Gangliosidosis Variants: Supplementing Traditional Biochemical Testing with Molecular Methods, Mayo Medical Laboratories Communique 2004 Jul;29(7) for more information regarding diagnostic strategy.


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

Useful For Suggests clinical disorders or settings where the test may be helpful

Carrier testing of individuals of Ashkenazi Jewish ancestry or who have a family history of Tay-Sachs disease


Determining carrier status for individuals with enzyme activity within the carrier or equivocal ranges


Prenatal diagnosis for at-risk families


Confirmation of suspected clinical diagnosis of Tay-Sachs disease in individuals of Ashkenazi Jewish ancestry

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This assay will not detect all of the mutations that cause Tay-Sachs disease. Therefore, the absence of a detectable mutation does not rule out the possibility that an individual is a carrier of or affected with this disease.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


In rare cases, DNA alterations of undetermined significance may be identified.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Gravel RA, Kaback MM, Proia RL, et al: The GM2 gangliosidosis. In The Metabolic and Molecular Bases of Inherited Disease. Eigth edition. Edited by CR Scriver, AL Beaudet, WS Sly, et al. New York, McGraw-Hill Book Company, available from URL: Accessed 3-18-10

2. Gross SJ, Pletcher BA, Monaghan KG: Carrier screening individuals of Ashkenazi Jewish descent. Genet Med 2008;10(1):54-56