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Mayo #8774 Hexosaminidase A and Total Hexosaminidase, Serum (Tay-Sachs)
Test Code8774
Alias/See Also
"B-N-Acetylglucosaminidase
Beta-N-Acetylglucosaminidase
GM2 Gangliosidosis
Hex A Deficiency
Hex B Deficiency
Hexosaminidase A Deficiency
Hexosaminidase B Deficiency
Hexosaminidase, Total
Sandhoff Carrier Screening
Sandhoff Carrier Testing
Sandhoff Disease
Beta-N-Acetylglucosaminidase
GM2 Gangliosidosis
Hex A Deficiency
Hex B Deficiency
Hexosaminidase A Deficiency
Hexosaminidase B Deficiency
Hexosaminidase, Total
Sandhoff Carrier Screening
Sandhoff Carrier Testing
Sandhoff Disease
CPT Codes
83080
Preferred Specimen
Serum/ red top 1 mL
Minimum Volume
0.5 mL
Other Acceptable Specimens
red/SST
Instructions
"1. Serum assay results are not valid on pregnant females and will not be run. If carrier screening for Tay-Sachs or Sandhoff disease is desired in a pregnant female and testing was not performed prior to pregnancy, refer to NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex or NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes for testing on the patient and partner.
2. The recommended test for Tay-Sachs carrier screening (regardless of gender or pregnancy status) is NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex.
"
2. The recommended test for Tay-Sachs carrier screening (regardless of gender or pregnancy status) is NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex.
"
Transport Container
Plastic vial
Specimen Stability
"Frozen (preferred) 30 days
Refrigerated 7 days
"
Refrigerated 7 days
"
Reject Criteria (Eg, hemolysis? Lipemia? Thaw/Other?)
This test cannot be performed on pregnant females
Methodology
Heat Inactivation, Fluorometric, Automated
Setup Schedule
Tuesday; 10:00 a.m
Report Available
8-15 days; retain for 30 days
Reference Range
"HEXOSAMINIDASE TOTAL, S
< or =15 years: > or =20 nmol/min/mL
> or =16 years: 10.4-23.8 nmol/min/mL
HEXOSAMINIDASE PERCENT A, S
< or =15 years: 20-90%
> or =16 years: 56-80%
"
< or =15 years: > or =20 nmol/min/mL
> or =16 years: 10.4-23.8 nmol/min/mL
HEXOSAMINIDASE PERCENT A, S
< or =15 years: 20-90%
> or =16 years: 56-80%
"
Clinical Significance
"Tay-Sachs disease and Sandhoff disease are lysosomal storage disorders, also referred to as GM2 gangliosidoses, caused by deficiencies of the enzymes hexosaminidase A and hexosaminidase B, respectively. These isoenzymes are dimers that differ in their subunit composition. Hexosaminidase A is a heterodimer composed of 1 alpha and 1 beta subunit (alpha-beta), while hexosaminidase B is a homodimer composed of 2 beta subunits (beta-beta). The defective lysosomal degradation and the excessive accumulation of GM2 ganglioside and related glycolipids results in the development of the clinical symptomology observed in Tay-Sachs and Sandhoff diseases.
Tay-Sachs Disease:
Tay-Sachs disease is caused by a deficiency of hexosaminidase A due to a defect in the alpha subunit. This autosomal recessive condition results from 2 mutations in the HEXA gene, which encodes for the alpha subunit of hexosaminidase. Individuals with Tay-Sachs disease have a deficiency in hexosaminidase A; those with 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. Patients exhibit weakness, hypotonia, and decreasing attentiveness. Motor skills learned previously, such as crawling or sitting alone, are nearly always lost by age 1. Other symptoms include rapid diminishing of vision, seizures, macroencephaly due to cerebral gliosis, and the characteristic cherry-red spot in the retina. Affected individuals typically do not survive past age 5.
The juvenile or subacute form of Tay-Sachs disease often presents between 2 and 10 years with ataxia and clumsiness. Patients develop difficulties with speech and cognition. Neurologic features progressively worsen and death is typically 2 to 4 years later.
Disease progression is slower in patients with chronic or adult-onset Tay-Sachs disease. Early signs and symptoms may be subtle and nonspecific, involving muscle and/or neurologic findings, often resulting in initial misdiagnoses. Affected individuals may exhibit abnormalities of gait and posture, spasticity, dysarthria (loss of speech), and progressive muscle wasting and weakness. Cognitive impairment, dementia, or psychiatric findings are observed in some patients. Significant clinical variability exists both between and within families.
The carrier frequency of Tay-Sachs disease is increased in certain groups including individuals of Ashkenazi Jewish, Celtic, and French Canadian ancestry. 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. Such sequence variations are not associated with disease, but result in the production of a hexosaminidase A enzyme with decreased activity towards the artificial substrate typically used in the enzyme assay. The recommended testing strategy is to order NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex, which begins with enzyme analysis and when the percent of hexosaminidase A enzyme is low, reflexes to the molecular panel which includes the most common mutations observed in these high-risk populations and 2 common pseudodeficiency alleles.
Sandhoff Disease:
Sandhoff disease (deficiency of hexosaminidase A and B due to a defect in the beta subunit) is an autosomal recessive condition resulting from 2 mutations in the HEXB gene, which encodes for the beta subunit of hexosaminidase. Individuals with Sandhoff disease have deficiencies in both hexosaminidase A and hexosaminidase B. Phenotypically, patients with Sandhoff disease present with features very similar to Tay-Sachs disease including variability in age of onset and severity. Enzyme analysis is generally required to distinguish between the 2 disorders. Unlike Tay-Sachs disease, Sandhoff disease does not have an increased carrier frequency in any specific population.
Diagnostic and Carrier Testing:
Testing for Tay-Sachs and Sandhoff diseases occurs by analysis of hexosaminidase A, a heat-labile enzyme, and total hexosaminidase (hexosaminidase A plus hexosaminidase B). When testing the enzyme, an artificial substrate is most commonly used. The total hexosaminidase is quantified. Following this, heat inactivation of hexosaminidase A occurs with a second measurement of the total enzyme level. From this, the percent hexosaminidase A is calculated. Biochemically, Tay-Sachs disease is characterized by normal total hexosaminidase with a very low percent hexosaminidase A. Carriers of Tay-Sachs disease are asymptomatic, but have intermediate percent hexosaminidase A in serum, leukocytes, and cultured fibroblasts. Follow-up molecular testing is recommended for all individuals with enzyme results in the carrier or possible carrier ranges to differentiate carriers of a pseudodeficiency allele from those with a disease-causing mutation. In addition, this allows for the facilitation of prenatal diagnosis for at-risk pregnancies.
A very small group of patients affected with Tay-Sachs disease have the B1 variant. In the presence of an artificial substrate, the B1 variant allows for a heterodimer formation of hexosaminidase A and exhibits activity. However, in vivo the B1 variant hexosaminidase A is inactive on the natural substrate. Thus, with the artificial substrate, these patients appear to be unaffected. Individuals with the B1 variant of Tay-Sachs disease must be distinguished using a natural substrate assay (MUGS / Hexosaminidase A (MUGS), Serum). This testing should be considered if one of the other assays indicates normal or carrier results and the suspicion of Tay-Sachs disease remains high.
Hexosaminidase testing using the artificial substrate provides an indirect assay for Sandhoff disease. Affected individuals exhibit very low total hexosaminidase with a disproportionately high percent hexosaminidase A due to alpha subunit homodimer formation. Carriers of Sandhoff disease are asymptomatic but have intermediate levels of total hexosaminidase with high percent hexosaminidase A in serum, leukocytes, and cultured fibroblasts. However, not all individuals with this pattern are true carriers of Sandhoff disease and follow-up molecular testing is recommended. In addition, molecular analysis allows for the facilitation of prenatal diagnosis for at-risk pregnancies. Testing hexosaminidase using the natural substrate does not identify homozygotes or heterozygotes for Sandhoff disease.
"
Tay-Sachs Disease:
Tay-Sachs disease is caused by a deficiency of hexosaminidase A due to a defect in the alpha subunit. This autosomal recessive condition results from 2 mutations in the HEXA gene, which encodes for the alpha subunit of hexosaminidase. Individuals with Tay-Sachs disease have a deficiency in hexosaminidase A; those with 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. Patients exhibit weakness, hypotonia, and decreasing attentiveness. Motor skills learned previously, such as crawling or sitting alone, are nearly always lost by age 1. Other symptoms include rapid diminishing of vision, seizures, macroencephaly due to cerebral gliosis, and the characteristic cherry-red spot in the retina. Affected individuals typically do not survive past age 5.
The juvenile or subacute form of Tay-Sachs disease often presents between 2 and 10 years with ataxia and clumsiness. Patients develop difficulties with speech and cognition. Neurologic features progressively worsen and death is typically 2 to 4 years later.
Disease progression is slower in patients with chronic or adult-onset Tay-Sachs disease. Early signs and symptoms may be subtle and nonspecific, involving muscle and/or neurologic findings, often resulting in initial misdiagnoses. Affected individuals may exhibit abnormalities of gait and posture, spasticity, dysarthria (loss of speech), and progressive muscle wasting and weakness. Cognitive impairment, dementia, or psychiatric findings are observed in some patients. Significant clinical variability exists both between and within families.
The carrier frequency of Tay-Sachs disease is increased in certain groups including individuals of Ashkenazi Jewish, Celtic, and French Canadian ancestry. 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. Such sequence variations are not associated with disease, but result in the production of a hexosaminidase A enzyme with decreased activity towards the artificial substrate typically used in the enzyme assay. The recommended testing strategy is to order NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex, which begins with enzyme analysis and when the percent of hexosaminidase A enzyme is low, reflexes to the molecular panel which includes the most common mutations observed in these high-risk populations and 2 common pseudodeficiency alleles.
Sandhoff Disease:
Sandhoff disease (deficiency of hexosaminidase A and B due to a defect in the beta subunit) is an autosomal recessive condition resulting from 2 mutations in the HEXB gene, which encodes for the beta subunit of hexosaminidase. Individuals with Sandhoff disease have deficiencies in both hexosaminidase A and hexosaminidase B. Phenotypically, patients with Sandhoff disease present with features very similar to Tay-Sachs disease including variability in age of onset and severity. Enzyme analysis is generally required to distinguish between the 2 disorders. Unlike Tay-Sachs disease, Sandhoff disease does not have an increased carrier frequency in any specific population.
Diagnostic and Carrier Testing:
Testing for Tay-Sachs and Sandhoff diseases occurs by analysis of hexosaminidase A, a heat-labile enzyme, and total hexosaminidase (hexosaminidase A plus hexosaminidase B). When testing the enzyme, an artificial substrate is most commonly used. The total hexosaminidase is quantified. Following this, heat inactivation of hexosaminidase A occurs with a second measurement of the total enzyme level. From this, the percent hexosaminidase A is calculated. Biochemically, Tay-Sachs disease is characterized by normal total hexosaminidase with a very low percent hexosaminidase A. Carriers of Tay-Sachs disease are asymptomatic, but have intermediate percent hexosaminidase A in serum, leukocytes, and cultured fibroblasts. Follow-up molecular testing is recommended for all individuals with enzyme results in the carrier or possible carrier ranges to differentiate carriers of a pseudodeficiency allele from those with a disease-causing mutation. In addition, this allows for the facilitation of prenatal diagnosis for at-risk pregnancies.
A very small group of patients affected with Tay-Sachs disease have the B1 variant. In the presence of an artificial substrate, the B1 variant allows for a heterodimer formation of hexosaminidase A and exhibits activity. However, in vivo the B1 variant hexosaminidase A is inactive on the natural substrate. Thus, with the artificial substrate, these patients appear to be unaffected. Individuals with the B1 variant of Tay-Sachs disease must be distinguished using a natural substrate assay (MUGS / Hexosaminidase A (MUGS), Serum). This testing should be considered if one of the other assays indicates normal or carrier results and the suspicion of Tay-Sachs disease remains high.
Hexosaminidase testing using the artificial substrate provides an indirect assay for Sandhoff disease. Affected individuals exhibit very low total hexosaminidase with a disproportionately high percent hexosaminidase A due to alpha subunit homodimer formation. Carriers of Sandhoff disease are asymptomatic but have intermediate levels of total hexosaminidase with high percent hexosaminidase A in serum, leukocytes, and cultured fibroblasts. However, not all individuals with this pattern are true carriers of Sandhoff disease and follow-up molecular testing is recommended. In addition, molecular analysis allows for the facilitation of prenatal diagnosis for at-risk pregnancies. Testing hexosaminidase using the natural substrate does not identify homozygotes or heterozygotes for Sandhoff disease.
"
