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Test ID: NAGR Hexosaminidase A and Total, Leukocytes/Molecular Reflex

Reporting Name

Hexosaminidase A and Tot, WBC/Mole

Useful For

Carrier detection and diagnosis of Tay-Sachs disease (see also NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes and NAGS / Hexosaminidase A and Total Hexosaminidase, Serum for additional testing options).

 

Recommended test for carrier detection of Tay-Sachs disease

 

Carrier detection and diagnosis of Sandhoff disease (testing option-not the recommended test)

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
TSDP Tay-Sachs, Mutation Analysis Yes No

Testing Algorithm

If hexosaminidase A is <63%, then TSDP / Tay-Sachs Disease, Mutation Analysis, HEXA will be added and performed at an additional charge.

 

The following algorithms are available in Special Instructions:     

Tay-Sachs Disease Carrier Testing Protocol

Tay-Sachs and Related Disorders Diagnostic Testing Algorithm

Specimen Type

Whole Blood ACD


Shipping Instructions


For optimal isolation of leukocytes, it is recommended the specimen arrive refrigerated within 96 hours of draw to be stabilized. Draw specimen Monday through Thursday only and not the day before a holiday. Specimen should be drawn and packaged as close to shipping time as possible.



Specimen Required


Container/Tube:

Preferred: Yellow top (ACD solution B)

Acceptable: Yellow top (ACD solution A)

Specimen Volume: 6 mL

Collection Instructions: Do not transfer blood to other containers.


Specimen Minimum Volume

5 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood ACD Refrigerated (preferred) 4 days
  Ambient  4 days

Reference Values

HEXOSAMINIDASE TOTAL

≤15 years: ≥20 nmol/min/mg

≥16 years: 16.4-36.2 nmol/min/mg

 

HEXOSAMINIDASE PERCENT A

≤15 years: 20-80% of total

≥16 years: 63-75% of total

Day(s) and Time(s) Performed

Specimens are stabilized Monday through Sunday

Assay is performed Monday, Thursday, and alternating Fridays; 8 a.m. (not reported on Saturday or Sunday)

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

Hexosaminidase A and Total, Leukocytes/Molecular Reflex
83080 x 2

Tay-Sachs Disease, Mutation Analysis, HEXA (if appropriate)

81255

LOINC Code Information

Test ID Test Order Name Order LOINC Value
NAGR Hexosaminidase A and Tot, WBC/Mole In Process

 

Result ID Test Result Name Result LOINC Value
8775 Hexosaminidase Total, WBC 24075-4
2294 Hexosaminidase Percent A, WBC 23825-3
2284 Interpretation (NAGW) 59462-2
35029 Reviewed By No LOINC Needed

Clinical Information

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, indeterminate, 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.

Interpretation

Interpretation is provided with report.

 

Hexosaminidase A usually composes greater than 62% of the total hexosaminidase activity in leukocytes (normal = 63%-75% A).

 

In leukocytes, the percent Hex A is used in determining whether an individual is a carrier of or affected with Tay-Sachs disease:

-63% to 75% hexosaminidase A is normal (noncarrier)

-58% to 62% hexosaminidase A is indeterminate (molecular testing recommended to discern carriers from non-carriers and to allow for prenatal diagnosis if desired)

-less than 58% hexosaminidase A is a carrier (molecular testing recommended to discern disease-causing mutations from pseudodeficiency alleles and to allow for prenatal diagnosis if desired)

-less than 20% hexosaminidase A is consistent with a diagnosis of Tay-Sachs disease.

 

In leukocytes, the total hexosaminidase in combination with the percent hexosaminidase A aids in determining whether an individual is at-risk to be a carrier of or is affected with Sandhoff disease:

-greater than or equal to 76% hexosaminidase A is suggestive of a Sandhoff carrier, when the total hexosaminidase is depressed

-Total hexosaminidase activity near zero with nearly 100% hexosaminidase A is consistent with Sandhoff disease

Clinical Reference

1. Triggs-Raine BL, Feigenbaum ASJ, Natowicz M, et al: Screening for carriers of Tay-Sachs disease among Ashkenazi Jews-A comparison of DNA-based and enzyme-based tests. N Engl J Med 1990;323:6-12

2. Delnooz CCS, Lefeber DJ, Langemeijer SMC, et al: New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. J Neurol Neurosurg Psychiatry 2010;81(9):968-972

3. Vallance H, Morris TJ, Coulter-Mackie M, et al: Common HEXB polymorphisms reduce serum HexA and HexB enzymatic activities, potentially masking Tay-Sachs disease carrier identification. Mol Genet Metab 2006 Feb;87(2):122-127

4. Kaback MM, Desnick RJ. Hexosaminidase A Deficiency. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. Seattle, WA, University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1218/

5. Neudorfer O, Pastores GM, Zeng BJ, et al: Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med 2005 Feb;7(2):119-123

6. Sutton VR: Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstet Gynecol Clin North Am 2002 Jun;29(2):287-296

7. D'Souza G, McCann CL, Hedrick J, et al: Tay-Sachs disease carrier screening: a 21-year experience. Genet Test 2000;4(3):257-263

Analytic Time

4 days

Method Name

Heat Inactivation, Fluorometric, Semiautomated

Forms

1. Biochemical Genetics Patient Information (T602) in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

3. If not ordering electronically, complete, print, and send a Molecular Genetics Request Form (T245: available from the supply catalog)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

mml-biochemical