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Test ID NAGW Hexosaminidase A and Total Hexosaminidase, Leukocytes

Reporting Name

Hexosaminidase A and Total, WBC

Useful For

Carrier detection and diagnosis of Tay-Sachs disease

 

Carrier detection and diagnosis of Sandhoff disease

Specimen Type

Whole Blood ACD


Ordering Guidance


Testing for Tay-Sachs Disease and Sandhoff Disease

The following tests are available for diagnostic and carrier testing for Tay-Sachs and Sandhoff diseases. 

 

NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex, Whole Blood:

-This is the recommended test for carrier testing for Tay-Sachs disease and Sandhoff disease.

-Testing begins with hexosaminidase A and total enzyme analysis. If the results are consistent with an affected or carrier for Tay-Sachs disease or Sandhoff disease, next generation sequencing to detect single nucleotide and copy number variants for HEXA or HEXB, respectively, will automatically be performed on the original specimen.

-This test is appropriate for males and pregnant or nonpregnant females.

 

NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes (this test):

-This test can be used for diagnosis and carrier testing for Tay-Sachs disease or Sandhoff disease.

-Results for hexosaminidase A and total enzyme analysis are reported with recommendations for additional testing when appropriate. All follow-up testing must be ordered separately on new specimens.

-This test is appropriate for males and pregnant or nonpregnant females.

 

NAGS / Hexosaminidase A and Total Hexosaminidase, Serum:

-This test can be used for diagnosis and carrier testing for Tay-Sachs disease or Sandhoff disease.

-Results for hexosaminidase A and total enzyme analysis are reported with recommendations for additional testing when appropriate.

-If results indicate normal, indeterminate, or carrier status and the suspicion of Tay-Sachs disease remains high, MUGS / Hexosaminidase A, Serum for Tay-Sachs disease -B1 variant can typically be added and performed on the same specimen.

-With the exception of MUGS, all follow-up testing must be ordered separately on new specimens.

-This test is not appropriate for pregnant females or women receiving hormonal contraception. This test is appropriate for males and nonpregnant females.

-This test is particularly useful when it is difficult to obtain enough blood to perform leukocyte testing (NAGR or NAGW), as may be the case with infants.

 

MUGS / Hexosaminidase A, Serum:

-This is the recommended test for diagnosis and carrier testing for the B1 variant of Tay-Sachs disease. This test will not detect Sandhoff disease.

-This test should not be ordered as a first-line test. Rather, this test should be ordered when the NAGR, NAGW, NAGS indicate normal, indeterminate, or carrier results, and the suspicion of Tay-Sachs disease remains high. In most cases, this test can be performed on the original specimen collected for NAGS.



Shipping Instructions


For optimal isolation of leukocytes, it is recommended the specimen arrive refrigerated within 6 days of collection to be stabilized. Collect specimen Monday through Thursday only and not the day before a holiday. Specimen should be collected 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: Send specimen in original tube. Do not aliquot.


Specimen Minimum Volume

5 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Whole Blood ACD Refrigerated (preferred) 6 days YELLOW TOP/ACD
  Ambient  6 days YELLOW TOP/ACD

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) Performed

Preanalytical processing: Monday through Saturday

Assay performed: Friday

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 US Food and Drug Administration.

CPT Code Information

83080 x 2

LOINC Code Information

Test ID Test Order Name Order LOINC Value
NAGW Hexosaminidase A and Total, WBC 87544-3

 

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 18771-6

Clinical Information

Tay-Sachs and Sandhoff diseases, also referred to as GM2 gangliosidoses, are lysosomal storage disorders 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 and Sandhoff diseases are autosomal recessive conditions. Tay-Sachs disease results from 2 variants in HEXA, which encodes for the alpha subunit of hexosaminidase, and causes a deficiency of hexosaminidase A enzyme. An increased carrier frequency for Tay-Sachs disease is observed in individuals of Ashkenazi Jewish, Celtic, and French-Canadian ancestry. Patients with Sandhoff disease have 2 variants in HEXB, which encodes for the beta subunit of hexosaminidase, and results in deficiencies in both hexosaminidase A and hexosaminidase B enzymes. Sandhoff disease does not exhibit an increased carrier frequency in any specific population.

 

Clinical Phenotypes:

Phenotypically, patients with Tay-Sachs and Sandhoff diseases are clinically indistinguishable. Variability is observed with respect to age of onset and clinical symptoms. Enzyme analysis is generally required to distinguish between the 2 disorders.

 

The acute infantile forms of Tay-Sachs and Sandhoff diseases typically present 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 1 year of age. Other symptoms include rapid diminishing of vision, seizures, macrocephaly due to cerebral gliosis, and the characteristic cherry-red spot in the retina. Affected individuals typically do not survive past 5 years of age.

 

The juvenile or subacute forms often present between 2 and 10 years of age with ataxia and clumsiness. Patients develop difficulties with speech and cognition. Neurologic features progressively get worse, and death typically occurs 2 to 4 years later. 

 

Disease progression is slower in patients with chronic or adult-onset Tay-Sachs and Sandhoff diseases. 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, 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.

 

Testing Options:

Several tests are available for the detection of carriers of and individuals affected with Tay-Sachs and Sandhoff diseases (see table below and Testing Algorithms). The recommended test for both diagnostic and carrier testing is NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex, Whole Blood. Testing begins with enzyme analysis and when indicated reflexes to the appropriate molecular analysis (either HEXA or HEXB gene) which includes sequencing and deletion/duplication analysis.

 

Follow-up molecular testing is recommended for all individuals with enzyme results in the carrier, possible carrier, or affected ranges. This differentiates between non-disease causing pseudodeficiency alleles and disease-causing variants. In addition, molecular analysis allows for the facilitation of carrier testing and prenatal diagnosis for at-risk individuals.

 

Test ID

Test Name

Tay-Sachs disease

Sandhoff disease

Reflexes to molecular genetic testing

Use during pregnancy or hormonal contraception

Preferred use

Carrier

Affected

Carrier

Affected

NAGR

Hexosaminidase A and Total, Leukocytes/Molecular Reflex, Whole Blood

Yes

Yes

Yes

Yes

Yes

Yes

Diagnostic or carrier testing

NAGW

Hexosaminidase A and Total Hexosaminidase, Leukocytes

Yes

Yes

Yes

Yes

No

Yes

Diagnostic or carrier testing

NAGS

Hexosaminidase A and Total Hexosaminidase, Serum

Yes

Yes

Yes

Yes

No

No

Diagnostic

MUGS*

Hexosaminidase A, Serum

Yes

Yes

No

No

No

No

Diagnostic, secondary only

 

*MUGS testing should be utilized only when one of the other assays indicates normal, indeterminate, or carrier results and the clinical suspicion of Tay-Sachs disease remains high.

Interpretation

Interpretation is provided with report.

 

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 Sep;81(9):968-972

3. Vallance H, Morris TJ, Coulter-Mackie M, Lim-Steele J, Kaback M: 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. Toro C, Shirvan L, Tifft C: HEXA disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 1999. Updated October 1, 2020. Accessed March 29, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1218/

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

6. Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K, Suzuki K: The GM2 gangliosidoses. In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed January 30, 2020. Available at https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225547784

Report Available

4 to 8 days

Method Name

Heat Inactivation, Fluorometric, Semi-Automated

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

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

3. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.