Tay-Sachs disease is a rare, inherited metabolic disease that mostly affects young children and involves progressive damage to and death of cells, particularly in the brain. It is caused by a mutation in the enzyme hexosaminidase A, which allows the harmful buildup of lipids (fatty materials such as oils and acids) in cells. Both parents must carry the mutated gene in order to have a child with Tay-Sachs disease. Tay-Sachs disease is part of a group of genetic disorders called the GM₂ gangliosidoses.

Affected children appear to develop without a problem until about 6 months of age and then begin to show neurological symptoms, including:

• Slowing of development
• Progressive loss of mental ability
• Dementia
• Blindness
• Increased startle reflex to noise
• Progressive loss of hearing leading to deafness
• Swallowing difficulty
• Seizures that may begin in the child's second year
• Cherry-red spots in their eyes

A much rarer form of the disorder, called late-onset Tay-Sachs disease, occurs in individuals in their 20s and early 30s and is characterized by an unsteady gait (manner of walking) and progressive neurological deterioration.

The incidence of Tay-Sachs disease has been particularly high among people of Eastern European and Ashkenazi Jewish descent, as well as in certain French Canadians and Louisiana Cajuns. Affected individuals and carriers of Tay-Sachs disease can be identified by a blood test that measures hexosaminidase A activity. A very severe form of Tay-Sachs disease, known as Sandhoff disease, is not limited to any ethnic group.

Presently there is no specific treatment for Tay-Sachs disease. Anticonvulsant medicine may initially control seizures. Other supportive treatment includes proper nutrition and hydration and techniques to keep the airway open. Children may eventually need a feeding tube.

Variants in the HEXA gene cause Tay-Sachs disease. The HEXA gene provides instructions for making one part (the alpha subunit) of an enzyme called beta-hexosaminidase A. Beta-hexosaminidase A is located in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside found in cell membranes.

HEXA gene variants affect the ability of the beta-hexosaminidase A enzyme to break down GM2 ganglioside. As a result, GM2 ganglioside accumulates to toxic levels, particularly in neurons in the central nervous system. Damage caused by the buildup of GM2 ganglioside leads to the dysfunction and eventual death of these neurons, which causes the signs and symptoms of Tay-Sachs disease.

HEXA gene variants that eliminate or severely reduce beta-hexosaminidase A enzyme function likely lead to the infantile form of Tay-Sachs disease, and variants that allow some residual enzyme activity tend to cause the juvenile or late-onset form of the condition.

Because Tay-Sachs disease impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.

Tay-Sachs disease (TSD) is a fatal genetic disorder, most commonly occurring in children, that results in progressive destruction of the nervous system. Tay-Sachs is caused by the absence of a vital enzyme called hexosaminidase-A (Hex-A). Without Hex-A, a fatty substance, or lipid, called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. This ongoing accumulation causes progressive damage to the cells.

In children, the destructive process begins in the fetus early in pregnancy. However, a baby with Tay-Sachs disease appears normal until about six months of age when its development slows. By about two years of age, most children experience recurrent seizures and diminishing mental function. The infant gradually regresses, and is eventually unable to crawl, turn over, sit or reach out. Eventually, the child becomes blind, cognitively impaired, paralyzed and non-responsive. By the time a child with Tay-Sachs is three or four years old, the nervous system is so badly affected that death usually results by age five.

A much rarer form of Tay-Sachs, Late-Onset Tay-Sachs disease, affects adults and causes neurological and intellectual impairment. Only recently identified, the disease has not been extensively described. As for the childhood form of Tay-Sachs, there is no cure. Treatment involves managing the symptoms of the disease.

Defect in Hex-A Gene Causes Tay-Sachs:

Tay-Sachs disease results from defects in a gene on chromosome 15 that codes for production of the enzyme Hex-A. We all have two copies of this gene. If either or both Hex-A genes are active, the body produces enough of the enzyme to prevent the abnormal build-up of the GM2 ganglioside lipid. Carriers of Tay-Sachs - people who have one copy of the inactive gene along with one copy of the active gene - are healthy. They do not have Tay-Sachs disease but they may pass on the faulty gene to their children.

Carriers have a 50 percent chance of passing on the defective gene to their children. A child who inherits one inactive gene is a Tay-Sachs carrier like the parent. If both parents are carriers and their child inherits the defective Hex-A gene from each of them, the child will have Tay-Sachs disease. When both parents are carriers of the defective Tay-Sachs gene, each child has a 25 percent chance of having Tay-Sachs disease and a 50 percent chance of being a carrier.

Eastern European (Ashkenazi) Jews at Greater Risk for Tay-Sachs Disease:

While anyone can be a carrier of Tay-Sachs, the incidence of the disease is significantly higher among people of eastern European (Ashkenazi) Jewish descent. Approximately one in every 27 Jews in the United States is a carrier of the Tay-Sachs disease gene. Non-Jewish French Canadians living near the St. Lawrence River and in the Cajun community of Louisiana also have a higher incidence of Tay-Sachs. For the general population, about one in 250 people are carriers.

There is no cure or effective treatment for Tay-Sachs disease. However, researchers are pursuing several approaches to finding a cure. Scientists are exploring enzyme replacement therapy to provide the Hex-A that is lacking in babies with Tay-Sachs. Bone marrow transplantation has been attempted also, but to date has not been successful in reversing or slowing damage to the central nervous system in babies with Tay-Sachs. Another avenue of research is gene therapy in which scientists transfer a normal gene into cells to replace an abnormal gene. This approach holds great promise for future Tay-Sachs patients.

Normal Function

The HEXA gene provides instructions for making one part (subunit) of an enzyme called beta-hexosaminidase A. Specifically, the protein produced from the HEXA gene forms the alpha subunit of this enzyme. One alpha subunit joins with one beta subunit (produced from the HEXB gene) to form a functioning beta-hexosaminidase A enzyme.

Beta-hexosaminidase A plays a critical role in the brain and spinal cord (central nervous system). This enzyme is found in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A forms part of a complex that breaks down a fatty substance called GM2 ganglioside found in cell membranes.

Health Conditions Related to Genetic Changes

Tay-Sachs disease

More than 210 variants (also known as mutations) that cause Tay-Sachs disease have been identified in the HEXA gene. Tay-Sachs disease is a condition that is characterized by movement disorders, intellectual and developmental disability, and other neurological problems caused by the death of nerve cells (neurons) in the central nervous system.

The HEXA gene variants that cause Tay-Sachs disease eliminate or severely reduce the activity of the enzyme beta-hexosaminidase A. This lack of enzyme activity prevents the enzyme from breaking down GM2 ganglioside. As a result, this substance builds up to toxic levels, particularly in neurons in the central nervous system. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these cells, which causes the signs and symptoms of Tay-Sachs disease.

Most of the known HEXA gene variants result in a completely nonfunctional version of beta-hexosaminidase A. These variants cause a severe form of Tay-Sachs disease, known as infantile Tay-Sachs disease, which appears in infancy. Other variants severely reduce but do not eliminate the activity of beta-hexosaminidase A. These genetic changes are responsible for less severe forms of Tay-Sachs disease, known as the juvenile and late-onset forms, which appear later in life.

Other Names for This Gene

• Beta-hexosaminidase A
• beta-N-Acetylhexosaminidase A
• Hex A
• HEXA_HUMAN
• hexosaminidase A (alpha polypeptide)
• N-acetyl-beta-glucosaminidase

Genomic Location

• 1 in 4 chance to have the disease
• 1 in 2 chance to be an unaffected carrier like each parent
• 1 in 4 chance to be unaffected and not a carrier

A simple blood test can identify Tay-Sachs carriers. Blood samples can be analyzed by either enzyme assay or DNA studies. The enzyme assay is a biochemical test that measures the level of Hex-A in a person's blood. Carriers have less Hex-A in their body fluid and cells than non-carriers.

DNA-based carrier testing looks for specific mutations or changes in the gene that codes for Hex-A. Since 1985, when the Hex-A gene was isolated, more than 50 different mutations in this gene have been identified. Nevertheless, some mutations are not yet known. The current tests detect about 95 percent of carriers of Ashkenazi Jewish background and about 60 percent of carriers in the general population.

If both parents are carriers, they may want to consult with a genetic counselor for help in deciding whether to conceive or whether to have a fetus tested for Tay-Sachs. Extensive carrier testing of Ashkenazi Jews has significantly reduced the number of Tay-Sachs children in this population group. Today most cases of Tay-Sachs disease occur in populations thought not to be at high risk.

Prenatal testing for Tay-Sachs can be performed around the 11th week of pregnancy using chorionic villi sampling (CVS). This involves removing a tiny piece of the placenta. Alternatively, the fetus can be tested with amniocentesis around the 16th week of pregnancy. In this procedure, a needle is used to remove and test a sample of the fluid surrounding the baby.

Assisted reproductive therapy is an option for carrier couples who don't want to risk giving birth to a child with Tay-Sachs. This new technique used in conjunction with in-vitro fertilization enables parents who are Tay-Sachs carriers to give birth to healthy babies. Embryos created in-vitro are tested for Tay-Sachs genetic mutations before being implanted into the mother, allowing only healthy embryos to be selected.

Tay-Sachs disease is very rare in the general population. The genetic variants (also known as mutations) that cause this disease are more frequently found in people of Ashkenazi (eastern and central European) Jewish heritage than in those with other backgrounds. However, increased education and genetic testing efforts in these at-risk communities have reduced the incidence of this condition in those populations.

The variants responsible for this disease are also more common in certain French-Canadian communities of Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population of Louisiana.