Tay-Sachs disease

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 caused by mutations in the HEXA gene. The HEXA gene provides instructions for making part of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord. This enzyme 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.^[3]

Mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, which prevents the enzyme from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in neurons in the brain and spinal cord. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these neurons, which causes the signs and symptoms seen in Tay-Sachs disease.^[3]

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

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.