Genetic Disorders - Tay-sachs Disease

Tay-Sachs disease (TSD) is caused by mutations in the HEXA gene, located on the long arm of chromosome 15. (See Figure 5.21.) It is a fatal genetic disorder in children that causes the progressive destruction of the central nervous system. It is caused by the absence of an important enzyme called hexosaminidase A (hex-A). Without hex-A, a fatty substance called GM2 ganglioside builds up abnormally in the cells, particularly the brain's nerve cells. (Figure 5.22 shows how the absence of, or defect in, the hex-A protein prevents complete processing of GM2 ganglioside.) Eventually, these cells degenerate and die. This destructive process begins early in the development of a fetus, but the disease is not usually diagnosed until the baby is several months old. By the time a child with TSD is four or five years old, the nervous system is so badly damaged that the child dies.

TSD was named for Warren Tay (1843–1927), a British ophthalmologist who first described a patient with a cherry-red spot on the retina of the eye that has become a hallmark of TSD, and Bernard Sachs (1858–1944), a New York neurologist who provided the first description of the cellular changes in TSD. Dr. Sachs also recognized the inheritance pattern of the disorder and observed that most cases of Tay-Sachs disease occurred in families of eastern European Jewish origin.

Symptoms of TSD

A baby with TSD seems normal at birth and usually develops normally for about the first six months of life, but then development slows. The child begins to regress and loses skills one by one—the ability to crawl, to sit, to reach out, and to turn over. The victim gradually becomes blind, deaf, and unable to swallow. The muscles begin to atrophy and paralysis sets in. Mental retardation occurs, and the child is unable to relate to the outside world. Death usually occurs between ages three and five. There is no cure or treatment for this disease.

How Is TSD Inherited?

TSD is an autosomal recessive genetic disorder caused by mutations in both alleles of the HEXA gene on chromosome 15. Both the mother and the father must be carriers of the defective TSD gene in order to produce a child with the disease.

People who carry the gene for TSD are entirely unaffected and usually unaware that they have the potential to pass this disease to their offspring. A blood test distinguishes Tay-Sachs carriers from noncarriers. Blood samples may be analyzed by enzyme assay or DNA studies. Enzyme assay measures the level of hex-A in blood. Carriers have less hex-A than noncarriers. When only one parent is a carrier, the couple will not have a child with TSD. When both parents carry the recessive TSD gene, they have a one in four chance in every pregnancy of having a child with the disease. They also have a 50% chance of bearing a child who is also a carrier. Prenatal diagnosis early in pregnancy can predict if the unborn child has TSD. If the fetus has the disease, the couple may choose to terminate the pregnancy.

Who Is at Risk?

Some genetic diseases, such as TSD, occur most frequently in a specific population. As Dr. Sachs observed, individuals of east European (Ashkenazi) Jewish descent have the highest risk of being carriers of TSD. According to the National Tay-Sachs and Allied Diseases Association, approximately one in twenty-seven Jews in the United States are carriers of the TSD gene, and 85% of the children who are victims of this disease are Jewish. Italians also have a higher than average risk of being carriers. In the general population, the carrier rate is one in 250.