Test Id : NAGR

If result interpretation is consistent with carrier, indeterminate, or affected for Tay-Sachs disease or Sandhoff disease, then next-generation sequencing to detect single nucleotide and copy number variants for HEXA or HEXB, respectively, will be performed at an additional charge.

See Tay-Sachs and Related Disorders Diagnostic Testing Algorithm

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 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.

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.

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.

• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Tay-Sachs and Related Disorders Diagnostic Testing Algorithm
• Informed Consent for Genetic Testing (Spanish)

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Biochemical Genetics Patient Information (T602)

3. If not ordering electronically, complete, print, and send an Inborn Errors of Metabolism Test Request (T798) with the specimen.

5 mL

Carrier detection and diagnosis of Tay-Sachs disease

Carrier detection and diagnosis of Sandhoff disease

If result interpretation is consistent with carrier, indeterminate, or affected for Tay-Sachs disease or Sandhoff disease, then next-generation sequencing to detect single nucleotide and copy number variants for HEXA or HEXB, respectively, will be performed at an additional charge.

See Tay-Sachs and Related Disorders Diagnostic Testing Algorithm

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 and Testing Algorithms). This test is the recommended test for both diagnostic and carrier testing. Testing begins with enzyme analysis and when indicated reflexes to the appropriate molecular analysis (either HEXA or HEXB gene), which includes next-generation sequencing to detect single nucleotide and copy number variants.

Follow-up molecular testing is recommended for all individuals with enzyme results in the carrier, possible carrier, or affected ranges. This differentiates between nondisease 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.

Table

*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.

HEXOSAMINIDASE TOTAL

< or =15 years: > or =20 nmol/min/mg

> or =16 years: 16.4-36.2 nmol/min/mg

HEXOSAMINIDASE PERCENT A

< or =15 years: 20-80% of total

> or =16 years: 63-75% of total

Interpretation is provided with report.

A small percentage (<0.5%) of carriers may exhibit normal hexosaminidase A activity and will not be detected by this method.(1)

GM2 activator deficiency (AB variant, GM2A) is a rare disorder with clinical features similar to Tay-Sachs and Sandhoff diseases; however, levels of both hexosaminidase A and B are normal. GM2 activator deficiency is not detected with this assay. Molecular genetic analysis of GM2A is available, see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

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 Jul;323(1):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, 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. 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, 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. 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. Accessed January 30, 2020. Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225547784

8. 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

• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Tay-Sachs and Related Disorders Diagnostic Testing Algorithm
• Informed Consent for Genetic Testing (Spanish)

Leukocyte hexosaminidase A and total hexosaminidase are estimated using a semiautomated modification of the method of O'Brien, et al (1970) with further specific recommendations on specimen preparation as outlined by the International Tay-Sachs Disease Testing Quality Control and Data Collection Center.(O'Brien JS, Okada S, Chen A, Fillerup DL: Tay-Sachs disease: detection of heterozygotes and homozygotes by hexosaminidase assay. N Engl J Med. 1970;283:15-20; Cowan T, Pasquali M: Laboratory investigations of inborn errors of metabolism. In: Sarafoglou K, Hoffman GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed. McGraw-Hill; 2017:1139-1158)

Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of variants in coding regions and intron/exon boundaries of the gene analyzed, as well as some other regions that have known pathogenic variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for indels less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction (PCR)-based quantitative method is performed to test for the presence of deletions and duplications in the gene analyzed.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.(Unpublished Mayo method)

Preanalytical processing occurs Monday through Saturday.

Assay is performed: Friday

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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.

83080 x2

81406 (if appropriate)

81479 (if appropriate)

Sample Reports

Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports

International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports