Tay-Sachs Disease: Causes, Diagnosis, and Prevention

Tay-Sachs disease is a rare genetic disorder that is typically constrained to certain ethnic populations. It is characterized by the destruction of nerve cells in the central nervous system and can lead to blindness, deafness, and the loss of mental and physical functions.

Tay-Sachs is an autosomal recessive disorder, meaning that it is a disease inherited from one’s parents. The disease is associated with mutations in the HEXA gene of which there are more than 100 variations. Depending on which mutations are paired, the disease can take vastly different forms, causing illness during infancy, childhood, or adulthood.

Death usually occurs in children within a few years of the first symptoms, as the destruction of nerve cells leaves them unable to move or even swallow. In the advanced stages, children will become increasingly prone to infection. Most die from complications of pneumonia or other respiratory infections.

While rare in the general population, Tay-Sachs is seen more frequently in Ashkenazi Jews, Cajuns of southern Louisiana, French Canadians of Southern Quebec, and Irish Americans.

How It Causes Illness

The HEXA gene provides instructions for making a type of enzyme known as hexosaminidase A. This enzyme is responsible for breaking down a fatty substance known as GM2 ganglioside.

In persons with Tay-Sachs disease, hexosaminidase A no longer functions as it should. Without the means to break down these fats, toxic levels begin to accumulate in the nerve cells of the brain and spinal cord, eventually destroying them and leading to the symptoms of the disease.

Infantile Tay-Sachs Disease

The signs and symptoms of Tay-Sachs disease vary by when the symptoms first develop.

The most common type is infantile Tay-Sachs disease, the first signs of which will appear between the ages of 3 and 6 months. This is the time when parents will start to notice that their child’s development and movements have markedly slowed.

By this stage, the child may be unable to turn over or sit up. If the child is older, they may have difficulty crawling or lifting an arm.

They will also exhibit an exaggerated, startled reaction to loud noises and may appear listless or lethargic. From there, the deterioration of mental and physical functions is usually relentless and profound.

Symptoms typically include:

• Seizures
• Vision loss and blindness
• Hearing loss and deafness
• Drooling and difficulty swallowing (dysphagia)
• Muscle stiffness and spasticity
• Muscle atrophy
• Loss of intellectual and cognitive function
• Paralysis
• Death

Death, even with the best of medical care, usually occurs before the age of 4.

Less Common Forms

While infantile Tay-Sachs is the predominant form of the disease, there are less common types seen in children and adults. The timing of the onset of the disease is largely related to the combination of genes inherited from the parents.

Of the two less common forms:

• Juvenile Tay-Sachs disease usually manifests with symptoms anywhere from 2 to 10 years of age. As with infantile Tay-Sachs, the progression of the disease is unremitting, leading to deterioration of cognitive skills, speech, and muscle coordination, as well as dysphagia and spasticity. Death usually occurs between 5 and 15 years.
• Late-onset Tay-Sachs disease (also known as adult Tay-Sachs) is extremely rare and will usually develop in adults between the ages of 30 and 40. Unlike the other forms of the disease, it is usually not fatal and will stop progressing after a certain amount of time. During this time, a person may experience a decline in mental skills, unsteadiness, speech difficulties, dysphagia, spasticity, and even a schizophrenia-like psychosis. Persons with late-onset Tay Sachs can often become permanently disabled and require a full-time wheelchair.

Genetics and Inheritance

As with any autosomal recessive disorder, Tay-Sachs occurs when two parents who don’t have the disease each contribute a recessive gene to their offspring. The parents are considered “carriers” because they each have one dominant (normal) copy of the gene and one recessive (mutated) copy of the gene. It is only when a person has two recessive genes that Tay-Sachs can occur.

If both parents are carriers, a child has a 25% chance of inheriting two recessive genes (and getting Tay-Sachs), a 50% chance of getting one dominant and one recessive gene (and becoming a carrier), and a 25% chance of getting two dominant genes (and remaining unaffected).

Because there are well over 100 variations of the HEXA mutation, different recessive combinations can end up meaning vastly different things. In some cases, a combination will confer to earlier onset and faster disease progression and, in other cases, later onset and slower disease progression.

While scientists are closer to understanding which combinations relate to which forms of the disease, there are still large gaps in our genetic understanding of Tay-Sachs in all of its forms.

Risk

As rare as Tay-Sachs is in the general population—occurring in around one of every 320,000 births—the risk is considerably higher in certain populations.

The risk is largely constrained to so-called “founder populations” in which groups can trace the roots of the disease back to a specific, common ancestor. Due to the lack of genetic diversity within these groups, certain mutations are passed more readily to offspring, resulting in higher rates of autosomal diseases.

With Tay-Sachs, we see this with four specific groups:

• Ashkenazi Jews have the highest risk of Tay-Sachs, with one of every 30 persons being a carrier. The specific type of mutation seen within the population (called 1278insTATC) leads to infantile Tay-Sachs disease. In the United States, one of every 3,500 Ashkenazi babies will be affected.
• Cajuns in southern Louisiana are also affected by the same mutation and have more or less the same level of risk. Scientists have been able to trace the ancestry of carriers back to the 18th century to a single founder couple in France who were not Jewish.
• French Canadians in Quebec have the same risk as Cajuns and Ashkenazi Jews but are affected by two entirely unrelated mutations. Within this population, one or both mutations are believed to have been brought from Normandy or Perche to the colony of New France sometime around the 17th century.
• Irish Americans are less commonly affected but still have around a one in 50 chance of being a carrier. The risk appears to be greatest among couples who have at least three Irish grandparents between them.

Diagnosis

Beyond the motor and cognitive symptoms of the disease, one of the telltale signs in children is an eye abnormality called a “cherry spot.” The condition, characterized by an oval, red discoloration on the retina, is easily spotted during a routine eye exam.

The cherry spot is seen in all infants with Tay-Sachs disease as well as some children. It is not seen in adults.

Based on the family history and the appearance of symptoms, the doctor will confirm the diagnosis by ordering blood tests to assess the levels of hexosaminidase A, which will either be low or non-existent. If there is any doubt about the diagnosis, the doctor can perform a genetic test to confirm the HEXA mutation.

Treatment

There is no cure for Tay-Sachs disease. Treatment is primarily directed at the management of symptoms, which may include:

• Anti-seizure medications such as gabapentin or lamotrigine
• Antibiotics to prevent or treat aspiration pneumonia
• Chest physiotherapy to treat respiratory congestion
• Physical therapy to keep the joints flexible
• Medications such as trihexyphenidyl or glycopyrrolate to control production of saliva and prevent drooling
• Use of baby bottles designed for children with cleft palates to aid in swallowing
• Muscle relaxants like diazepam to treat stiffness and cramping
• Feeding tubes either delivered through the nose (nasogastric) or surgically implanted into the stomach (percutaneous endoscopic gastrostomy, or PEG tube)

While gene therapy and enzyme replacement therapy research are being explored as a means to cure or slow the progression of Tay-Sachs disease, most are in the very early stages of research.

Prevention

Ultimately, the only way to prevent Tay-Sachs is to identify couples who are at high risk and aid them in making the appropriate reproductive choices. Depending on the situation, an intervention may take place either before or during pregnancy. In some cases, there may be ethical or moral dilemmas to consider.

Among the options:

• During a pregnancy, amniocentesis or chorionic villus sampling can be used to retrieve fetal cells for genetic testing. Couples can then decide whether to have an abortion based on the results.
• Couples who are undergoing in vitro fertilization (IVF) can have the fertilized eggs genetically tested before implantation. By doing so, they can ensure that only healthy embryos are transferred to the womb. While effective, IVF is a very costly option.
• In orthodox Jewish communities, a group called Dor Yeshorim conducts anonymous screenings for Tay-Sachs disease in high school students. Persons who undergo the testing are given a six-digit identification code. When they find a potential mate, the couple can call a hotline and use their ID numbers to assess their “compatibility.” If both are carriers, they would be designated as “incompatible.”

A Word From Verywell

If faced with a positive result for Tay-Sachs disease—either as a carrier or a parent—it is important to speak with a specialist physician to fully understand what the diagnosis means and what your options are.

There are no wrong or right choices, just personal ones for which you and your partner have every right to confidentiality and respect.