Tay-Sachs Disease, HEXA Gene, Full Gene Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Tay-Sachs disease (TSD) is an inherited lysosomal storage disease caused by a deficiency of the enzyme beta-hexosaminidase A. It is characterized by accumulation of GM2 gangliosides in cells of the brain and central nervous system. The HEXA gene encodes the alpha subunit of beta-hexosaminidase A and mutations in this gene cause TSD. TSD occurs in approximately 1 in 200,000 live births with a carrier frequency of 1/250 to 1/300 in the general population. The carrier frequency for this disease in individuals of Ashkenazi Jewish ancestry is 1/31.
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 include progressive neurodegeneration, seizures, and blindness, leading to total incapacitation and death. The subacute and adult-onset types of TSD are characterized by later ages of onset and a broad spectrum of disease symptoms and severity.
TSD is inherited in an autosomal recessive manner. Several common mutations in the HEXA gene account for 92% of disease-causing mutations in the Ashkenazi Jewish population. Testing for these mutations is available as a panel, TSD / Tay-Sachs Disease, Mutation Analysis, HEXA. In non-Ashkenazi Jewish individuals, the detection rate for the common mutations is significantly decreased. Sequencing of the entire HEXA gene detects less common disease-causing mutations.
The recommended first-tier test for TSD carrier screening and diagnosis in all patients is a biochemical test that measures hexosaminidase A activity in white blood cells, NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes. 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 testing strategy.
Second-tier test for confirming a biochemical diagnosis of Tay-Sachs disease (TSD)
Carrier testing of individuals with a family history of TSD but an affected individual is not available for testing or disease-causing mutations have not been identified
Testing individuals with enzyme activity consistent with carrier status but negative molecular testing by a panel of common mutations
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
A small percentage of individuals who are carriers or have a diagnosis of Tay-Sachs disease (TSD) may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of TSD. For carrier testing, it is important to first document the presence of a HEXA gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
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.
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.
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.
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. Eighth edition. Edited by CR Scriver, AL Beaudet, WS Sly, et al. New York, McGraw-Hill Book Company, 2001, pp 3827-3876
2. ACOG Committee on Genetics: ACOG Committee Opinion #318; Screening for Tay-Sachs disease. Obstet Gynecol 2005;106(4):893-894