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TSD
82588
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/82588 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/8775 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.
Useful For: Carrier testing of individuals for Tay-Sachs disease (TSD) when familial mutations have
been previously identified Diagnostic confirmation of TSD when familial mutations have been previously
identified Prenatal testing when 2 familial mutations have been previously identified in an affected family
member
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Gravel RA, Kaback MM, Proia RL, et al: The GM2 gangliosidosis. In The
Metabolic and Molecular Bases of Inherited Disease. 8th 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
Tay-Sachs Disease, Mutation Analysis, HEXA
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 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/8775 Hexosaminidase
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