Study type: Blood collected in a yellow-top [acid-citrate-dextrose (ACD)] or a red-top tube for hexosaminidase enzyme assay; lavender-top [EDTA], pink-top [K₂ EDTA] or yellow-top tube [ACD] for molecular PCR assay; related body system: Reproductive system. The specimen should be transported immediately to the laboratory for processing and analysis.

There are more than 70 lysosomal enzyme disorders. Hexosaminidase is a lysosomal enzyme, the deficiency of which results in accumulation of complex sphingolipids and gangliosides in the brain and spinal cord. The most studied isoenzymes are hexosaminidase A (one alpha and one beta subunit) and hexosaminidase B (two beta subunits); total and A hexosaminidases (plasma, serum, or leukocyte assays) are the studies recommended as first tier testing when investigating suspected Tay-Sachs or Sandhoff disease, both of which are autosomal recessive conditions.

Tay-Sachs disease results from two variants in the HEXA gene and is characterized by a progressive lack of physical and intellectual development that becomes noticeable between 3 and 6 mo of age. Patients who are homozygous for this trait have no hexosaminidase A; signs and symptoms include red spot in the retina, blindness, and muscular weakness. Tay-Sachs disease results in early death, usually between ages 2 to 5 years. Tay-Sachs disease is also known as GM2 gangliosidosis type 1. This enzyme deficiency is most common among Ashkenazi Jews, for whom the incidence is 1 in 3,000 and carrier rate is 1 in 30. An increased carrier frequency is also noted in individuals of Celtic and French-Canadian ancestry.

Sandhoff disease results from two variants in the HEXB gene. Because the HEXB gene is responsible for production of the beta subunit, decreased levels of both hexosaminidase A and B occur and result in accumulation of GM2 ganglioside. Sandoff and Tay-Sachs share many similarities in clinical symptoms and biochemical findings. Sandhoff disease prevalence is not associated with a specific ethnic population. Molecular testing for gene variants can differentiate between Tay-Sachs and Sandoff. Individuals with Sandhoff disease demonstrate low total hexosaminidase levels and a comparatively elevated percent of hexosaminidase A (due to formation of alpha subunits and absence of beta subunits).

Biochemical screening tests are used to measure enzyme activity in serum or in WBCs. Serum screening tests should be chosen for low-risk populations because molecular assays have less than 50% specificity in the low-risk and carrier populations. WBC screening tests should be chosen instead of serum screening tests for women who are pregnant, who are taking oral contraceptives, or who have severe liver or autoimmune disease because of the unreliability of test results in samples from these patients. Negative screening results may be further investigated for the presence of pseudodeficiency mutations, which are non–disease-causing mutations. Molecular testing should be ordered for confirmation when screening results are either inconclusive or indicative of carrier status. Genetic testing by DNA PCR analysis can identify as many as 94% of the gene mutations associated with Tay-Sachs disease in persons with Ashkenazi Jewish heritage, 80% of the mutations in persons with French-Canadian ancestry, and 25% of mutations in non-Jewish Caucasians.

Genetic testing combined with enzyme screening analysis and correlation of clinical information provides the most reliable means of determining carrier status. The American College of Obstetricians and Gynecologists Committee on Genetics recommends that preconceptual or prenatal screening be offered to both persons in a couple if both are of Ashkenazi Jewish, French-Canadian, or Cajun ancestry or to any person with a family history of Tay-Sachs disease. Counseling and written, informed consent are recommended and sometimes required before genetic testing.

Knowledge of genetics assists in identifying those who may benefit from additional education, risk assessment, and counseling. Genetics is the study and identification of genes, genetic mutations, and inheritance. For example, genetics provides some insight into the likelihood of inheriting a medical condition such as Tay-Sachs disease. Some conditions are the result of mutations involving a single gene, whereas other conditions may involve multiple genes and/or multiple chromosomes. Every person receives a copy of the HEXA gene from each parent. If each parent is a carrier, has one normal and one abnormal or mutated HEXA gene, the baby has a 25% chance of developing Tay-Sachs disease because the possible combinations are 25% normal (a normal gene provided from each parent), 50% normal/carrier (a normal gene from the father and an abnormal gene from the mother or a normal gene from the mother and an abnormal gene from the father), and 25% abnormal (an abnormal gene provided from each parent). Babies who inherit a normal and abnormal copy of the HEXA gene are also considered carriers because they provide the potential for transmitting the condition to the next generation. Further information regarding inheritance of genes can be found in the study titled “Genetic Testing.”