The hexosaminidases are a group of highly specialized enzymes which break down compounds called gangliosides, which are themselves derived from fatty substances called glycolipids.
Gangliosides are abundant on the outside of neurons (brain cells). Normally, they are constantly made and degraded, but when there is insufficient hexosaminidase activity, gangliosides accumulate and eventually kill the neuron. Once a neuron is dead, it cannot be replaced. Over time, so many neurons die that the brain can no longer work properly. Individuals with infantile Tay-Sachs disease appear normal at birth and develop as expected until 3 to 6 months of age. However, GM2 gangliosides are already accumulating in their neurons, and within the first year of life, the signs of the disease will become apparent. Frequently, the first indication of a problem is an exaggerated startle reflex, which can seem benign. This is followed over the next months by a rapidly progressive loss of previous developmental milestones, including head control, visual tracking of objects, rolling over, and sitting. Affected infants develop involuntary muscle twitches called myoclonic jerks, and most begin having seizures before they turn 2. Gangliosides accumulate in the retinal neurons, giving the fundus a distinct, pale appearance with sparing of the fovea. This causes a characteristic "cherry red spot" visible on fundoscopy, although this sign is not specific for Tay-Sachs disease. As the disease progresses, affected infants lose all skills, including voluntary movement, hearing, vision, and the ability to swallow. Nearly all individuals with the infantile form of the disease die before reaching 5 years old, commonly from pneumonia caused by aspiration of mucus or oral secretions.
Obviously, Tay-Sachs is a truly horrific disease and no parent should ever have to watch their baby slip away like that. Approximately 1 in 30 people of Ashkenazi Jewish ethnic background are asymptomatic carriers of Tay-Sachs disease, meaning they inherited one mutated and one normal copy of the HEXA gene. In the recent past, this meant that most patients diagnosed with Tay-Sachs were Jewish. However, the Jewish community have embraced genetic screening for the common "Jewish diseases". As a result, Ashkenazim no longer comprise the majority of patients affected with Tay-Sachs.
