Tay-Sachs Disease

In 1881 Warren Tay, a British ophthalmologist, observed a "cherry red spot" in the retina of a one-year-old child with mental and physical retardation. Later, in 1896 Bernard Sachs, an American neurologist, observed extreme swelling of neurons in autopsy tissue from affected children. He also noted that the disease seemed to run in families of Jewish origin. Both physicians were describing the same disease, but it was not until the 1930s that the material causing the cherry-red spot and neuronal swelling was identified as a ganglioside lipid and the disease could be recognized as an "inborn error of metabolism." The term "ganglioside" was coined because of the high abundance of the brain lipid in normal ganglion cells (a type of brain cell). In the 1960s, the structure of the Tay-Sachs ganglioside was identified and given the name "GM2 ganglioside" (Figure 1).

Gangliosides are glycolipids. The lipid component, called ceramide, sits in the membranes of cells. Attached to it and sticking out into the extra-cellular Figure 1. Molecular basis for Tay-Sachs disease. Absence of or defect in the Hex A protein prevents complete processing of GM2 ganglioside. space is a linked series of different sugars, the "glyco" portion of glycolipid. The basic function of gangliosides is not well understood, but they appear to have roles in biological processes as diverse as cell-to-cell recognition, differentiation, and in the repair of damaged neurons.

Gangliosides, like most cell components, are broken down and regenerated as part of normal cellular metabolism. The breakdown or "catabolism" of gangliosides occurs in the lysosome, a specialized vesicle that is analogous to the vacuole of plants. In the lysosome a series of acid hydrolases (degradative enzymes) removes each sugar, one at a time, until the ceramide lipid is all that remains. In Tay-Sachs disease, one of the lysosomal hydrolases, Hex A, is defective or completely absent, so the degradative process is blocked before completion. The result is the accumulation of G_M2 ganglioside, the last molecule before the Hex A block in the catabolic sequence.

Since breakdown is blocked while synthesis continues, the result is a progressive accumulation of GM2 ganglioside and massive swelling of the lysosomes and hence of the neurons containing them. This is the basis of Figure 2. The macular cherry-red spot on the eye is an indicator of Tay-Sachs disease, an autosomal recessive disease that affects the nervous system. the neuron swelling observed by Sachs and the cherry-red spot described by Tay. The cherry-red spot is due to the white appearance of swollen neurons of the retina surrounding the normally red fovea centralis (central depression in retina and site of maximum vision acuity) in the back of the eye (Figure 2).

Newborns with Tay-Sachs disease appear normal at birth. By six months of age, parents begin to notice that their infant is becoming less alert and is less responsive to stimuli. The affected infant soon begins to regress and shows increasing weakness, poor head control, and inability to crawl or sit. The disease continues to progress rapidly through the first years of life, with seizures and increasing paralysis. The child eventually progresses to a completely unresponsive vegetative state. Death is often caused by pneumonia because of the child's weakened state. Some forms of Tay-Sachs disease are much milder with onset of the disease later in childhood or even adulthood. We now know that these forms of the disease are caused by less severe mutations in the HEXA gene.