Tay Sachs Disease: Pathophysiology and Prevention

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Tay Sachs
Tay-Sachs disease is a devastating genetic lysosomal storage disease that affects infants and young children. One out of 320,000 births results in a Tay-Sachs-affected child, but the carrier rate in the general population is 1 in 250-300 individuals (Solovyeva et al.). In the Ashkenazi Jewish population, the carrier rate is 1 in 29 individuals. Tay-Sachs disease always results in the death of the affected child by the age of five, and it is devastating for all families affected by the disease. Therefore, knowledge about Tay-Sachs and its prevention is vital to decrease the rates of this deadly disease.
Tay Sachs disease results from a mutation in a specific gene known as the HEXA gene on chromosome 15. The HEXA gene typically codes for one protein subunit called beta-hexosaminidase A. Beta-hexosaminidase A typically leaves the endoplasmic reticulum, where it is formed and directed to the lysosome, breaking down GM2 gangliosides (Ramani and Parayil Sankaran). GM2 gangliosides are constantly being formed and broken down in healthy individuals, so beta-hexosaminidase A plays a significant role in ensuring that GM2 gangliosides continue to get broken down. However, in individuals with Tay-Sachs disease, a mutation in the HEXA gene on chromosome 15 leads to creation of a misfolded and non-functioning subunit of hexosaminidase A. Without proper functioning hexosaminidase A, the mutated protein cannot be brought into the lysosome and break down GM2 gangliosides as it typically should be able to do. With this mutation, GM2 gangliosides continue to be formed without them getting broken down. This allows for the accumulation of GM2 gangliosides in cells (Sumathy et al.). The massive buildup of GM2 gangliosides primarily affects nerve cells, and substantially increased levels of GM2 gangliosides lead to the death of these cells. Therefore, as an infant born with Tay-Sachs disease slowly grows older, the GM2 gangliosides continue to build up in their nerve cells, and the nerve cells in their brain and spinal cord slowly die, leading to the deterioration of function.
The pathophysiology of Tay-Sachs disease directly leads to devastating clinical consequences for children affected by the disease. GM2 gangliosides build up in the nerve cells, and cells within the nervous system begin to die (Chen et al.). However, when an infant is born, there has often not been too much of a buildup of GM2 gangliosides, so a Tay-Sachs child may appear perfectly normal at birth. When the infant grows older, more GM2 gangliosides begin to build up in the neurons, killing off these central nervous system cells. As these cells within the nervous system die, those affected by Tay-Sachs begin to experience symptoms. There is a loss of verbal and motor skills as well as a loss of movement control. Infants who could previously sit up, roll over, or make sounds, are no longer able to do so. This is because the neurons that allow the infant to carry out these functions die out due to the buildup of GM2 gangliosides, and the infant regresses their verbal and motor skills (Zhang et al.). Additionally, Tay-Sachs children may experience seizures due to massive disturbances to their central nervous system. Next, Tay-Sachs c...