History and Physical Findings
Lucy and Chris, a young and healthy, non-consanguineous couple, were expecting their first child. Genetic testing was not recommended, as they had no knowledge of heritable disease in their family histories. The fetus developed normally and a healthy baby girl named Ashley was born. She developed normally for the first six months at which point she had learned to roll over and lift her head, but her mother noticed that she was startled easily. Ashley subsequently started missing developmental milestones. Around the age of one, Ashley’s parents started noticing a developmental decline characterized by spastic movements of the limbs, stiff and flexed limbs, ...view middle of the document...
Confirmation of TSD diagnosis can be made based on HEXA enzyme assays using serum6,7. The disease occurs in instances when both parents are heterozygous and have donated a mutated HEXA allele to a child.
The prevalence of the disorder varies between different populations. In the United States, the Jewish community sees a higher frequency of TSD,1/6,000 births, than the non-Jewish population, 1/500,000 births, and the Ashkenazi Jews experience a higher frequency yet8. The incidence of TSD in Ashkenazi Jews is approximately 100 times greater than among non-Jews8. In North America, 1/31 Jewish individuals are Tay-Sachs carriers9. French Canadians also have 10 times the risk for Tay-Sachs as the general population10. However, due to increased awareness and genetic testing, the incidence rate of TSD in the Jewish populations throughout the United States and Canada has been greatly reduced as much as 90% since 19702.
Acid hydrolase activity is important for proper functioning and regulation of the body, failure or defect in this activity can result in lysosomal storage problems such as TSD11,12. β-hexosaminidase A (HEXA) is a crucial lysosomal enzyme, consisting of two subunits (α and β) which are encoded for by genes HEXA and HEXB. The responsibility of breaking down and hydrolyzing GM2 gangliosides fall to HEXA13. In TSD, any number of mutations could cause transcription of non-functional or incorrect HEXA enzyme proteins14. Without enough functioning HEXA, GM2 gangliosides begin to accumulate in the body’s central nervous system, primarily in the neurons’ lysosomes. With increased accumulation of GM2 gangliosides, the neurons become enlarged and abnormally shaped15. This accumulation is deleterious and causes eventual apoptosis of the cells, although a specific mechanism has not yet been determined11. Extensive demyelination accompanies neuron death in the brain in TSD cases15. The death of neuronal cells contributes to the neurological regression that takes place in a TSD patient, causing the markedly neurological issues with motor and brain function, including vision loss. The trademark ophthalmological sign of TSD is the “cherry red” spot that develops in the eye is due to the lipid-filled ganglion cells16.
Phenotype and Natural History
Tay-Sachs disease is divided into the three categories of infantile, juvenile, or late-adult onset, and displays variable expressivity as the severity of symptoms is inversely related to the time of life in which they are manifested17-23. This disorder also displays a pattern of complete penetrance when individuals are homozygous for the recessive allele18. On average, patients that acquire the infantile-onset form of this disorder begin displaying symptoms within the first five months of life and most die by the age of four from neurological degeneration complications17,24. The phenotypic features of infantile-onset Tay-Sachs disease include a red spot on the retina of the eye, low...