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PubMed This is a summary of 13 peer-reviewed journal articles Updated
Medical Genetics

Lab Results and Genetic Testing: Understanding the Pathology

At a Glance

Diagnosing GM2 gangliosidosis involves a two-step process: biochemical testing to measure Hex A and Hex B enzyme activity, followed by genetic testing to identify the exact mutations in the HEXA, HEXB, or GM2A genes that cause Tay-Sachs, Sandhoff disease, or the AB variant.

Understanding the pathology of GM2 gangliosidosis requires looking at two different “blueprints”: the protein machinery (enzymes) and the master instructions (genes). Most patients will undergo two types of testing—biochemical assays to see if the machinery is working, and molecular genetic testing to find the specific error in the instructions [1][2].

Step 1: The Enzyme Audit (Biochemical Testing)

The first step in the diagnostic journey is measuring the activity of beta-hexosaminidase A (Hex A) and beta-hexosaminidase B (Hex B) [1][3]. These are usually measured in leukocytes (white blood cells), which provide the most accurate reading [3].

When you look at your lab report, you will see patterns that point toward a specific diagnosis:

  • Tay-Sachs Disease: Low or absent Hex A activity, but normal Hex B activity [1][3].
  • Sandhoff Disease: Low or absent activity in both Hex A and Hex B [1][3].
  • AB Variant: Normal Hex A and Hex B activity. If a person has all the classic symptoms but normal enzyme levels, doctors must test for a deficiency in the GM2 activator protein (the GM2A gene) [3][4].

Understanding “Residual Activity”

In late-onset forms of the disease, the report may show “residual” activity—meaning the enzyme is present but only working at a fraction (often 1% to 5%) of its normal capacity [5]. This small amount of enzyme is why symptoms appear later in life rather than in infancy [5][6].

Step 2: The Genetic Confirmation (Molecular Testing)

Once an enzyme deficiency is found, molecular testing is used to identify the exact mutation. This is critical for family planning and for determining if the patient may be eligible for specific clinical trials [2][7].

  • Targeted Panels: These look for the most common mutations found in specific groups, such as the Ashkenazi Jewish or French-Canadian populations. In Ashkenazi Jewish individuals, these panels can detect about 98% of carriers [8].
  • Whole Exome Sequencing (WES) or Full Gene Sequencing: For individuals not from a high-risk group, targeted panels are less effective [8][9]. In these cases, full sequencing of the HEXA, HEXB, or GM2A genes is the gold standard for finding “private” or rare mutations [2][10].

A Note on “Pseudodeficiency”

Your report might mention pseudodeficiency alleles (like p.Arg247Trp). These are genetic variations that make the enzyme look low in a lab test even though the enzyme works perfectly fine in the body [11][12]. If your biochemical test is low but you have no symptoms, genetic testing is used to rule out these harmless variants [8][12]. This is an important detail that prevents false alarms for healthy individuals.

Completeness Checklist

To ensure your or your child’s diagnostic workup is thorough, your medical records should ideally include:

  • [ ] Enzyme Assay Report: Testing of Hex A and Hex B activity levels (preferably in leukocytes) [3].
  • [ ] Percentage Calculation: A calculation of “Percent Hex A” (Hex A activity divided by the total Hex A + B activity) [3].
  • [ ] Molecular/Genetic Report: Identification of two pathogenic (disease-causing) mutations in the HEXA, HEXB, or GM2A gene [2].
  • [ ] Clinical Correlation: A statement from a geneticist or neurologist connecting the lab findings to the physical symptoms (e.g., infantile vs. late-onset) [13].
  • [ ] Carrier Screening for Relatives: Information regarding testing for siblings (who have a high chance of being carriers) or other close family members [8].

If any of these pieces are missing, it is appropriate to ask your care team for a follow-up test or a referral to a biochemical geneticist.

Return to Home

Common questions in this guide

How do doctors test for Tay-Sachs and Sandhoff diseases?
Doctors use biochemical assays to measure the activity of Hex A and Hex B enzymes, usually in white blood cells. Tay-Sachs is indicated by low Hex A but normal Hex B activity, while Sandhoff disease involves low or absent activity in both enzymes.
What does residual enzyme activity mean on my pathology report?
Residual activity means the tested enzyme is present but only working at a fraction of its normal capacity, often between 1 and 5 percent. This small amount of functional enzyme is typically seen in late-onset forms of the disease rather than infantile forms.
Why would I need genetic sequencing if my enzyme test is normal?
If you have classic symptoms but normal Hex A and Hex B enzyme levels, you may have the AB variant. In this case, doctors will use genetic testing to check the GM2A gene for a deficiency in the GM2 activator protein.
What are pseudodeficiency alleles in genetic testing?
Pseudodeficiency alleles are harmless genetic variations that make enzyme levels appear low on a laboratory test, even though the enzymes function normally in your body. Genetic testing helps identify these variants to prevent false alarms in healthy individuals.
Why is targeted panel testing used for some people and full sequencing for others?
Targeted genetic panels look for specific, common mutations and are highly effective for high-risk populations, such as individuals of Ashkenazi Jewish or French-Canadian descent. For those not in these groups, full gene sequencing is often needed to find rare mutations.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Was the enzyme testing performed on leukocytes (white blood cells) or serum?
  2. 2.What was the 'Percentage of Hexosaminidase A' relative to the total Hexosaminidase activity?
  3. 3.If enzyme levels were normal, have we ruled out the AB variant through GM2A gene sequencing?
  4. 4.Were any 'pseudodeficiency alleles' identified that might complicate the interpretation of the results?
  5. 5.Do the mutations found in the genetic report (HEXA or HEXB) correlate with the infantile, juvenile, or late-onset form of the disease?

Questions For You

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References

References (13)
  1. 1

    Case of late-onset Sandhoff disease due to a novel mutation in the HEXB gene.

    Sung AR, Moretti P, Shaibani A

    Neurology. Genetics 2018; (4(4)):e260 doi:10.1212/NXG.0000000000000260.

    PMID: 30065954
  2. 2

    Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco.

    Bibi F, Ullah A, Bourinaris T, et al.

    Klinische Padiatrie 2021; (233(5)):226-230 doi:10.1055/a-1371-1561.

    PMID: 33831955
  3. 3

    GM2 gangliosidosis AB variant: novel mutation from India - a case report with a review.

    Sheth J, Datar C, Mistri M, et al.

    BMC pediatrics 2016; (16()):88 doi:10.1186/s12887-016-0626-6.

    PMID: 27402091
  4. 4

    GM2 activator deficiency: An ultra-rare disorder with a new case and review of 22 published cases.

    Yoldaş Çelik M, Köşeci B, Burgaç E, Yararbaş K

    Molecular genetics and metabolism reports 2025; (43()):101225 doi:10.1016/j.ymgmr.2025.101225.

    PMID: 40386041
  5. 5

    The diagnostic journey for patients with late-onset GM2 Gangliosidoses.

    Lopshire MC, Tifft C, Burns J, et al.

    Molecular genetics and metabolism reports 2023; (37()):101014 doi:10.1016/j.ymgmr.2023.101014.

    PMID: 38053937
  6. 6

    [Progressive psychomotor regression for 2.5 years in a boy aged 5 years].

    Tian MQ, Chen XX, Li L, et al.

    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2022; (24(6)):699-704 doi:10.7499/j.issn.1008-8830.2201048.

    PMID: 35762438
  7. 7

    Simultaneous surgery for gastrostomy and laryngotracheal separation in a patient with Tay‒Sachs disease.

    Moroto M, Daisuke U, Yodoi T, et al.

    Human genome variation 2024; (11(1)):43 doi:10.1038/s41439-024-00300-0.

    PMID: 39609393
  8. 8

    Prenatal Diagnosis of Tay-Sachs Disease.

    Zhang J, Chen H, Kornreich R, Yu C

    Methods in molecular biology (Clifton, N.J.) 2019; (1885()):233-250 doi:10.1007/978-1-4939-8889-1_16.

    PMID: 30506202
  9. 9

    Shortcomings of ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish ancestry.

    Llorin H, Tennen R, Laskey S, et al.

    Genetics in medicine open 2024; (2()):101869 doi:10.1016/j.gimo.2024.101869.

    PMID: 39669632
  10. 10

    Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene.

    Martins C, Brunel-Guitton C, Lortie A, et al.

    Molecular genetics and metabolism reports 2017; (11()):24-29 doi:10.1016/j.ymgmr.2017.01.017.

    PMID: 28417072
  11. 11

    Determination of frequencies of alleles, associated with the pseudodeficiency of lysosomal hydrolases, in population of Ukraine.

    Olkhovych NV, Gorovenko NG

    Ukrainian biochemical journal 2016; (88(5)):96-106 doi:10.15407/ubj88.05.096.

    PMID: 29235819
  12. 12

    Screening for Tay-Sachs disease carriers by full-exon sequencing with novel variant interpretation outperforms enzyme testing in a pan-ethnic cohort.

    Cecchi AC, Vengoechea ES, Kaseniit KE, et al.

    Molecular genetics & genomic medicine 2019; (7(8)):e836 doi:10.1002/mgg3.836.

    PMID: 31293106
  13. 13

    Diagnosing Late-Onset Tay-Sachs Through Next Generation Sequencing and Functional Enzyme Testing: From Genes to Enzymes.

    Tupil AR, Rivlin W, Mccombe PA, et al.

    Neurology. Genetics 2024; (10(6)):e200205 doi:10.1212/NXG.0000000000200205.

    PMID: 39807213

This page explains GM2 gangliosidosis lab tests and genetic testing terminology for educational purposes only. Always consult your genetic counselor or neurologist for a personalized interpretation of your specific lab reports.

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