INTRODUCTION — This monograph discusses implications of genetic test results for the HEXA gene, which encodes the alpha subunit of beta-hexosaminidase A, the enzyme that is deficient in Tay-Sachs disease (TSD).
It does not discuss indications for testing and is not intended to replace clinical judgment in decisions to test or care of the tested individual. These subjects are discussed separately . (See 'Resources' below.)
How to read the report — The table summarizes major considerations for the clinician reviewing the genetic test results (table 1). These include the importance of obtaining a hard copy or digital report rather than a verbal statement, confirming which person was tested, and determining whether the test evaluated a targeted panel of common variants or the entire HEXA gene.
Testing used to guide clinical care should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally or regionally certified laboratory. If not done initially and results are to be used in clinical decision-making, testing should be repeated in a certified clinical laboratory. Decision-making may be affected by positive results (expected or unexpected) or negative results in an individual at risk for carrying a disease variant. (See 'Epidemiology and inheritance' below.)
HEXA gene — HEXA encodes the alpha subunit of beta-hexosaminidase A (also called hexosaminidase A), an enzyme in lysosomes that breaks down gangliosides (glycolipids derived from neuronal membranes).
When enzyme activity is deficient, gangliosides accumulate inside neuronal lysosomes, causing neuronal cell death and progressive neurodegeneration. Tay-Sachs disease (TSD) is the resulting disease.
Absence (or near absence) of enzyme activity is required to damage neurons; neurons that have approximately half-normal activity are unaffected. Thus, TSD is autosomal recessive, requiring HEXA disease variant(s) on both paternally and maternally inherited genes (homozygosity or compound heterozygosity) (table 3).
Evaluation of HEXA can be done with either enzyme testing or DNA analysis.
●Enzyme assay – Enzyme testing generally has higher sensitivity than targeted sequence analysis. Enzyme testing is most often done on serum. Pregnancy elevates enzyme levels; testing in individuals who are pregnant or taking oral contraceptives should be done on peripheral blood leukocytes .
When enzyme testing is performed, it is important to be aware of HEXA variants that cause pseudodeficiency, a laboratory artifact with absent enzymatic activity in a standard assay but no clinical consequences. Two major pseudodeficiency variants have been well-characterized (c.739C>T and c.745C>T) . Individuals with reduced enzyme activity should be checked for these to determine whether the reduced activity is due to a pathogenic variant or a benign pseudodeficiency allele.
•Individuals heterozygous for a pseudodeficiency allele have reduced enzyme activity in vitro but are not carriers for TSD.
•Individuals with compound heterozygosity for a HEXA disease variant and a pseudodeficiency variant have severely deficient enzyme activity but are not affected with TSD; they are carriers.
Rarely, serum enzyme tests may yield inconclusive results that should be clarified with enzyme testing in leukocytes and/or DNA analysis.
●DNA analysis – Many pathogenic variants in HEXA have been described. Testing depends on the genetic background of the tested individual.
Three common pathogenic variants are seen in individuals of Eastern European (Ashkenazi) Jewish ancestry :
•c.1274_1277dupTATC (frameshift mutation that introduces premature stop codon)
•c.805G>A (replacement of glycine with serine at position 269)
•c.1421+1G>C (intronic variant causing abnormal splicing)
Variants in individuals of non-Ashkenazi backgrounds are spread throughout the HEXA gene.
In some cases, the clinical impact of a variant may be uncertain (variant of uncertain significance [VUS]), and enzyme testing may be required (table 4).
The hexosaminidase A enzyme is formed from an alpha and a beta subunit; the beta subunit is encoded by the HEXB gene. Sandhoff disease is a related disorder caused by disease variants in HEXB, which cause deficiency of two enzymes, hexosaminidase A and hexosaminidase B (formed from two beta subunits). These and other related disorders are summarized in the tables listing hereditary ataxias (table 5) and lysosomal storage disorders (table 6).
Epidemiology and inheritance — Tay-Sachs disease (TSD) is an autosomal recessive disorder (figure 1) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the HEXA gene .
Certain populations are known to have a higher carrier frequency for HEXA disease variants [5,6].
●Individuals of Ashkenazi Jewish background (Central and Eastern European Jews, most Jews in the United States) have a carrier frequency of approximately 1 in 30. With effective carrier screening, most families are aware of the familial variant and which family members are carriers. Three common variants are listed above. (See 'HEXA gene' above.)
●Certain other backgrounds have an increased carrier frequency, including French Canadian, Cajun from Louisiana, and Pennsylvania Dutch. A few common pathogenic variants have been detected in these populations.
Individuals in the general population can also carry pathogenic variants in HEXA; race and ethnicity cannot be used to exclude this risk. A negative family history also cannot be used to exclude HEXA variants; as with most autosomal recessive disorders, heterozygotes are unaffected and the family history is often unremarkable.
Clinical features and diagnosis — TSD is a neurodegenerative lysosomal storage disease and a form of hereditary ataxia.
The age of presentation varies but is typically in infancy. In the classical infantile presentation, motor development is normal during the first few months of life, with symptom onset at approximately five to six months of age.
Symptoms include incoordination, exaggerated startle response, loss of muscle tone, progressive neurologic deterioration, functional decline, and loss of previously-attained developmental milestones; the median survival is approximately four years .
The retinal cherry red spot (picture 1) typically develops between 3 and 12 months of age. It is caused by accumulated glycolipids in neuroretinal cells surrounding the macula. The spot is the normal color of the macula; pallor surrounding the macula creates the appearance. The cherry red spot is not specific for TSD; it can be seen in other neuronopathic lysosomal storage disorders. (See "Overview of the hereditary ataxias".)
Juvenile and adult-onset (also called late-onset) forms of TSD are less common. Typical ages of presentation are two to five years and adolescence to early adulthood, respectively. Adults with late-onset disease have a more variable course including psychosis and gait disturbance .
Following clinical assessment, diagnosis is made by serum testing for enzyme activity and/or genetic testing for HEXA variants. (See 'HEXA gene' above.)
●If enzyme activity is low or absent, it may be prudent to rule out pseudodeficiency using genetic testing.
●For a variant of uncertain significance (VUS), enzyme activity testing will help establish the pathogenicity.
●Individuals with abnormal clinical findings and negative HEXA testing will require additional evaluations for other conditions.
Most states in the United States do not perform newborn screening for TSD. (See "Newborn screening", section on 'Resources'.)
Management — Therapy for TSD primarily involves supportive care to reduce morbidities and preserve functional status.
●Pulmonary – Airway clearance therapies are used to reduce the risk of pneumonia. (See "Respiratory muscle weakness due to neuromuscular disease: Management".)
●Neurologic – Seizure management is often required. No specific medications or therapies are more effective in TSD than in idiopathic epilepsies. Physical therapy is used to maintain functional status. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
●Gastrointestinal – Constipation may occur and may be treated with standard approaches. (See "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment".)
●Psychiatric – Individuals with late-onset TSD may require antipsychotics or antidepressants. (See "Unipolar major depression in adults: Choosing initial treatment".)
Various disease-modifying approaches have been investigated, including restoring enzyme activity (enzyme replacement or gene therapy) or reducing the accumulated substrate (inhibiting glucosylceramide synthesis with miglustat); none have demonstrated efficacy. Approaches under consideration include targeted substrate reduction and enzyme replacement ligated to chaperones that cross the blood-brain barrier.
Parents of a child with TSD should receive genetic counseling (risks of having another affected child) and implications for their relatives. (See 'Partner testing' below and 'Asymptomatic adult' below.)
REPRODUCTIVE SCREENING AND TESTING — Identification of HEXA disease variants before conception is the primary means of avoiding Tay-Sachs disease (TSD).
According to the American College of Obstetricians and Gynecologists (ACOG), couples should be offered carrier screening for conditions for which they are at increased risk, or if they request screening .
Known familial variant — Individuals with a known pathogenic HEXA variant in the family can be tested for that variant to determine if they are carriers.
Ashkenazi Jewish ancestry — Individuals of Ashkenazi Jewish ancestry, including Jews from Eastern Europe (the ancestry of most American Jews), should have the opportunity to be screened prior to conception.
Screening can be done by genetic testing and/or enzyme testing. If genetic testing is used, assessment for the common Ashkenazi Jewish variants is generally adequate to identify or exclude carrier status. A negative screen using a panel of these variants can reduce residual risk to approximately 1 in 5800. Enzyme testing and full HEXA gene sequencing have slightly higher sensitivity than targeted mutation analysis. (See 'Epidemiology and inheritance' above.)
Non-Ashkenazi Jewish (or unknown) ancestry — Individuals from non-Ashkenazi Jewish backgrounds, including those of unknown ancestry, should have the opportunity to be screened prior to conception if they have any reason for concern about carrier status, including a genetic background with increased carrier frequency, possible TSD in the family, or other reasons. (See 'Epidemiology and inheritance' above.)
Screening can be done by enzyme testing followed by genetic testing if needed. Full-gene HEXA analysis or simultaneous enzyme and genetic testing can also be used. If enzyme testing shows reduced activity, pseudodeficiency is excluded by identification of a specific HEXA pseudodeficiency variant. (See 'HEXA gene' above.)
A negative screen by full HEXA gene sequencing can reduce residual risk to approximately 1 in 100,000. (See 'HEXA gene' above.)
Partner testing — Partner testing is appropriate for any couple in which one member tests positive for a pathogenic or likely pathogenic HEXA variant.
●The algorithm illustrates our approach (algorithm 1).
●The figure summarizes potential outcomes if the partner is also a carrier (figure 2).
If both partners are carriers, genetic counseling should be offered and information provided about assisted reproductive technologies (ART) and prenatal testing .
●ART may include use of donor gametes (egg or sperm) or in vitro fertilization (IVF) with preimplantation genetic testing (PGT) of embryos. (See "Preimplantation genetic testing".)
●Prenatal testing involves amniocentesis or chorionic villus sampling, results of which can be used to inform pregnancy options.
ASYMPTOMATIC ADULT — An asymptomatic adult who is heterozygous for a single pathogenic or likely pathogenic variant in HEXA is an unaffected carrier.
Their first-degree relatives typically have a 50 percent chance of also carrying the variant and should be informed of this, especially if they are considering childbearing (or may do so in the future).
Second-degree relatives (table 7) who may consider childbearing may also benefit from this information, although it is preferable to test first-degree relatives initially, if possible, followed by cascade testing if needed. (See "Genetics: Glossary of terms", section on 'Cascade testing'.)
Testing of relatives at risk of carrier status can be deferred to childbearing age to allow the most meaningful counseling and informed consent. (See 'Reproductive screening and testing' above.)
Counseling coordinated among family members may be advantageous to ensure that all receive comprehensive information and appropriate testing, which may be limited to testing for the specific familial variant in at-risk relatives.
•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).
•Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide virtual (online or telephone) access to a genetic counselor.
●Patient support – National Tay-Sachs & Allied Diseases Association (NTSAD).
•Tay Sachs disease (TSD)/hereditary ataxias – (See "Overview of the hereditary ataxias".)
•Preconception/prenatal screening – (See "Preconception and prenatal carrier screening for genetic disease more common in people of Ashkenazi Jewish descent and others with a family history of these disorders".)
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