Tay-Sachs Disease 2011

Summary

The Tay-Sachs disease (TSD) is a rare autosomal, recessive genetic disorder which is caused by accumulation of lipids in the brain. This leads to the cell death of those neurons. There exist three different variations of the TSD. The most common one is the Infantile Tay-Sachs disease which results in death of the children under the age of 5. The two other variants are the Juvenile and Adult/Late Onset TSD, which are less aggressive. The disease causes a deterioration of mental and physical abilities. Sadly, there currently exists no treatment.

Phenotype

Infantile Tay-Sachs disease:

The most common and aggressive form of TSD is the infantile TSD, which has a wide range of different symptoms and leads to the early death of the affected children. The most common symptoms are:

normal development in the first six month after birth
"cherry-red" macula
paralysis
dementia
blindness
deafness
muscle atrophy
startle response to sound stimuli
inability to coordinate muscle movement (child can't roll over and sit)
death in the second or third year

Juvenile and Adult TSD:

This forms of the Tay-Sachs disease occur later in lifetime. These two forms were not always recogniced as variants of the TSD. The symptoms of these forms are less aggressive. Often the patients become wheelchair users and have some psychiatric and physical limitation, which can be handled with drugs.

Cross-references

Biochemical disease mechanism

The affecting protein in the TSD is the Beta-Hexosaminidase, which is a heterodimer consisting of two subunits alpha (encoded by the gene HEXA) and beta (encoded by the gene HEXB). The alpha subunit processes the hydrolysis of the GM2 gangliosides (which are fatty acid derivatives) to the GM3 gangliosides (compare Figure 1 and Figure 2). This means the enzyme gradates the lipids in the brain and in other tissues. If the enzyme is defect it results in the accumulation of GM2 gangliosides in the neurons, which results the death of those cells.

Figure 1: KEGG-Pathway Glycosphingolipid biosynthesis highlighting TSD associated enzyme Beta-Hexosaminidase A (http://www.genome.jp/tmp/mark_pathway130536834226114/hsa00604.png)

Figure 2: Catalytic mechanism for Beta-Hexosaminidase A.. Disclaimer: This file is redistributed from [M. Joanne Lemieux, Brian L. Mark, Maia M. Cherney, Stephen G. Withers, Don J. Mahuran3, and Michael N. G. James . Crystallographic Structure of Human β-Hexosaminidase A: Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis. J Mol Biol. Author Manuscript 2010;] . All rights belong to the creator.

Cross-references

Mutations

Only mutations in the HEXA gene (the protein is visualized in Figure 3) can result in the TSD, whereas mutations in the HEXB gene result in other metabolic diseases. Today, there are more than 120 known mutations which cause the TSD disease. These mutations suppress the activity of the Beta-Hexosamidase A which causes the failure of the GM2 gangliosides degradation. Furthermore, this leads to the toxic accumulation of those lipids which results in the cell death of the involved neurons. The TSD is normally very rare, but there is a strong prevalence for it in the Eastern European Jewish, Cajun and French Canadian population. Most of the mutations in HEXA lead to the TSD, because they delete the enzyme function completely, which cause the infantile form of TSD. There are other mutations, which only reduce the enzyme-activity and therefore, cause the Juvenile or Adult TSD.