Tay-Sachs disease

Tay-Sachs disease is a rare, inherited neurodegenerative disease. People with Tay-Sachs disease do not have enough of an enzyme called beta-hexosaminidase A.  The less enzyme a person has, the more severe the disease and the earlier that symptoms appear. There are 3 forms of Tay-Sachs disease, distinguished by the general age of onset:^[1][2]

• Infantile - the most common severe form, with symptoms appearing in the first few months of life. Symptoms include a loss of skills learned (regression), seizures, and loss of muscle and mental functions. Children with this form do not survive past early childhood.
• Juvenile - a form with a range of severity, with symptoms appearing any time during childhood (but usually between ages 2 and 5). Symptoms include behavior problems, gradual loss of skills, frequent respiratory infections, and seizures. People with this form typically do not survive past their teenage years.
• Late onset/adult - the least severe form, with symptoms appearing in late childhood to adulthood. Symptoms may include clumsiness, muscle weakness, psychiatric disorders, and gradual loss of skills, often leading to the need for mobility assistance. Intellect and behavior become impaired in some cases. The lifespan varies from shortened to unaffected.

Tay-Sachs disease is caused by mutations in the HEXA gene and inheritance is autosomal recessive. The HEXA gene gives the body instructions to make part of the beta-hexosaminidase A enzyme, which is needed to break down a substance called GM2 ganglioside. When the enzyme is not functional or not made, GM2 ganglioside builds up in the nerve cells (neurons) of the brain and spinal cord, causing the symptoms of the disease.^[3]

The diagnosis of Tay-Sachs disease involves a blood test that detects absent or very low levels of beta-hexosaminidase A enzyme activity. Molecular genetic testing of the HEXA gene may be used to identify the specific mutations present, or to rule out the disease if a false-positive blood test result is suspected.^[4]

Currently there is no cure for Tay-Sachs disease, and there are no therapies that slow the progression of the disease. Treatment aims to relieve symptoms and increase quality of life. For example, children with seizures may be treated with anti-seizure medicines. Adequate nutrition and hydration are recommended, to prevent complications.^[4][5]

Note: You may also find Tay-Sachs disease referred to as a lysosomal storage disease or a GM2-gangliosidosis because the disease involves a lysosomal enzyme and the buildup of GM2 ganglioside.

Tay-Sachs disease is inherited in an autosomal recessive manner.^[3] This means that to have the disease, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have Tay-Sachs disease.

People with Tay-Sachs disease inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disease typically do not have any signs or symptoms (they are "unaffected"). When 2 carriers of an autosomal recessive disease have children, each child has a:

• 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

The first symptoms of Tay-Sachs disease may appear from infancy to adulthood, depending on how much beta-hexosaminidase A enzyme activity a person has (if any).

In the most common form, the infantile form, infants have no enzyme activity, or an extremely low level (less than 0.1%). They typically appear healthy in the newborn period, but develop symptoms within 3 to 6 months of age. The first symptom may be an exaggerated startle response to noise. Infants with this form begin to lose milestones such as rolling and sitting (regression) and develop muscle weakness, which gradually leads to paralysis. They also lose mental functions and become increasingly unresponsive to their surroundings. By 12 months of age, they begin to deteriorate more rapidly, developing blindness, seizures that are hard to treat, and difficulty swallowing. Infants with this form of Tay-Sachs disease typically do not survive past 4 years of age. The most common cause of death is complications from lung inflammation (bronchopneumonia).^[1][2][5]

The juvenile form is less common and is characterized by having very little enzyme activity, typically less than 1% of normal activity. Depending on exactly how much activity there is, symptoms may begin any time during childhood, most commonly between ages 2 and 5.  Children with this form often develop frequent infections, behavioral problems, and have more slowly progressive loss of movement control, speech, and mental function. They may also begin to have seizures and lose their vision. Children with the juvenile form often spend several years having no responsiveness or awareness before passing away in late childhood or adolescence. Infection is a common cause of death.^[1][2][5]

The late onset form, sometimes called the adult or chronic form, is also less common and is characterized by having less than 10% of normal enzyme activity. Symptoms and severity vary more among people with this form. Symptoms may begin in childhood to adulthood, but the disease is often not diagnosed until adolescence or adulthood. Neurological impairment is slowly progressive and may lead to clumsiness and loss of coordination, muscle weakness, tremors, difficulty speaking or swallowing, and uncontrollable muscle spasms and movements. Many people eventually need mobility assistance. In some people with this form, the first obvious symptom is a severe psychiatric disorder such as schizophrenia. Impaired intellect or dementia may or may not develop. Some people with the late onset form have a shortened lifespan due to the disease, while others do not.^[1][2][5]

Tay-Sachs disease is very rare in the general population. The genetic mutations that cause this disease are more common in people of Ashkenazi (eastern and central European) Jewish heritage than in those with other backgrounds. The genetic mutations that cause Tay-Sachs disease are also more common in certain French-Canadian communities of Quebec, some Amish groups, and the Cajun community of Louisiana.^[3]

Currently, there is no cure for Tay-Sachs disease, and there is no treatment that stops or slows the progression of the disease. Treatment aims to relieve some of the symptoms, manage infections, prevent complications, and increase quality of life as much as possible. Treatment for symptoms may include anticonvulsants to control seizures in children, and antipsychotic medications for psychiatric disorders in adults. Of note, tricyclic antidepressants are thought to be ineffective, and they may actually inhibit the little enzyme activity that may be present in some people with the disease. Preventing complications involves getting adequate nutrition and hydration, preventing airway obstruction, and avoiding severe constipation with food additives, stool softeners, or laxatives.^[4][5] Research into potential treatments for Tay-Sachs disease is ongoing.

Central nervous system enzyme replacement or neuronal-corrective gene therapy are experimental considerations for treatment of Tay -Sachs disease at present, but are only at the theoretical stage clinically. A genetically engineered mouse model of infantile Tay -Sachs disease has been constructed and is now being used to evaluate innovative treatment modalities. Most recently, clinical trials have been initiated, utilizing enzymatic inhibitors which block (reduce) the biosynthesis of glycoshingolipids such as GM2 ganglioside . One such agent, N- deoxynigiromycin , has shown some efficacy with the non-CNS neuronal storage disorder, type I Gaucher disease.^[6][7]