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y 4 years. Tay-Sachs disease is an autosomal recessive condition resulting from 2 mutations in the
HEXA gene on 15q23-24, which encodes for the alpha subunit of hexosaminidase. Individuals with
Tay-Sachs disease have a deficiency in hexosaminidase A, though those that have higher residual enzyme
activity may have a milder clinical presentation with a later age of onset. The acute infantile form
typically presents with progressive motor deterioration beginning at 3 to 6 months of age and death
typically occurs by 4 years. The juvenile or subacute form often presents with ataxia and incoordination
between 2 and 10 years with progressive worsening of symptoms and death typically 2 to 4 years later.
The chronic or adult-onset subtype may present with motor weakness or psychiatric manifestations in
adulthood. The carrier frequency of Tay-Sachs disease is increased in the Ashkenazi Jewish population
(1/31). There are 3 null alleles with increased frequency in the Ashkenazi Jewish population that in either
homozygous or compound heterozygous state are known to be associated with classical Tay-Sachs disease
(1278insTATC, G269S, IVS12+1G->C). The G269S allele results in a higher residual enzyme activity
and in either a homozygous or compound heterozygous state results in the adult-onset form of Tay-Sachs
disease. In addition, IVS9+1G->A and 7.6 kbdel 5'UTR-IVS+1 are mutations 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 1 of 2 pseudodeficiency alleles, 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. The molecular genetics panel offered by
Mayo Medical Laboratories includes the 7 above-mentioned mutations (TSD/82588 Tay-Sachs Disease,
Mutation Analysis, HEXA). Sandhoff disease is an autosomal recessive condition resulting from 2
mutations in the HEXB gene on 5q13, which encodes for the beta subunit of hexosaminidase. Individuals
with Sandhoff disease have deficiencies in both hexosaminidase A and hexosaminidase B. Enzymatic
testing can be used for diagnostic purposes, but individuals with possible carrier status for Sandhoff
disease must be confirmed with molecular sequence analysis of the HEXB gene. Unlike Tay-Sachs
disease, Sandhoff does not have an increased carrier frequency in individuals with Ashkenazi Jewish
ancestry. If both partners are found to be carriers and a pregnancy is at risk for either disease, mutations
must first be identified if prenatal testing is desired. Please refer to NAGR/82943 Hexosaminidase A and
Total, Leukocytes/Molecular Reflex or NAGW/8775 Hexosaminidase A and Total Hexosaminidase,
Leukocytes for carrier detection and diagnosis of Tay-Sachs disease. Refer to Carrier Testing for
Tay-Sachs Disease and Other GM2 Gangliosidosis Variants: Supplementing Traditional Biochemical
Testing with Molecular Methods, MML Communique 2004 Jul;29(7) for more information regarding
diagnostic strategy (article available online at
MayoMedicalLaboratories.com/media/articles/communique/mc2831-0704.pdf.) See Tay-Sachs Disease
Carrier Testing Protocol algorithm in Special Instructions.
Useful For: Diagnosing Tay-Sachs disease, carriers of Tay-Sachs, Sandhoff disease, and carriers of
Sandhoff disease
Interpretation: Interpretation is provided with report. Hexosaminidase A (Hex A) usually makes up
>62% of the total hexosaminidase activity in leukocytes (normal =63% to 75% A). The key factor for
determining whether an individual is a carrier of or affected with Tay-Sachs disease is the percent Hex A:
63% to 75% A is normal (noncarrier) 58% to 62% Hex A in leukocytes is ambiguous (molecular testing
recommended to discern carriers from noncarriers and to allow for prenatal diagnosis)