Tay-Sachs disease is a genetic disorder that belongs to GM2 Gangliosidoses which a group of three related genetic disorders includes Tay-Sachs disease, Sandhoff disease, and activator deficiency. All of these disorders arise from the defects of ganglioside metabolism. Tay-Sachs disease shows autosomal recessive inheritance pattern.

Incidence

In Tay-Sachs disease, disease-causing alleles are found at extremely higher in Ashkenazi Jews than other populations. About 1 in 27 Ashkenazi Jews is a carrier of a Tay-Sachs allele, and the incidence of affected infants is 100 times higher than in other populations. The incidence of Tay-Sachs disease ranges from 1 in 3600 Ashkenazi Jewish births to 1 in 360.000 non-Ashkenazi Jewish North American births. Therefore, this disease also classified “pan-ethnic”. The most likely explanation for this situation is “Founder Effect”. This hypothesis states that when a small number of individuals from a larger population establish a new population, genetic diversity and variations may decline.

Pathogenesis

Gangliosides are ceramide oligosaccharides and present in all cell surface membranes but most abundant in the brain, especially in neuronal dendrites and axon termini. They function as receptors for various glycoprotein hormone and are involved in cell differentiation and cell-cell interaction. Tay-Sachs disease caused by the deficiency of an enzyme called Hexosaminidase A that break down the GM2 gangliosides and sphingolipids. The absence of this enzyme leads to excess accumulation of ganglioside GM2 and related glycolipids in the lysosome, as a result, causes neuronal death.

Structure of GM2 Ganglioside

There are three isoenzymes of Hexosaminidase; Hex S which comprise of two α subunits, HexA which comprise of one α and one β subunit, and HexB which comprise of two β subunits. These isoenzymes catalyze different reactions so, are responsible for different tasks and HexA implicated in Tay-Sachs disease. For the HexA to function properly it also needs activator protein in addition to subunits. In other words, three genes required for HexA activity and the diseases that result from defects in each of the genes.

GM2 Gangliosidoses

Clinical Manifestations

The clinical manifestations of defects in the three genes are indistinguishable except that there is also the involvement of the visceral organs such as hepatosplenomegaly in Sandhoff disease.

Tay-Sachs disease has three distinct forms; Infantile-onset, Juvenile-onset, and Adult-onset. Infantile-onset Tay-Sachs disease has a grim course. Affected infants appear normal until about 3 to 6 months. Then, neurological degeneration begins and progress to death by 2 to 4 years. Motor development of infants interrupted by neuronal death and begins to regress until to loss of voluntary movement in the first two years. Visual loss begins within the first year and progresses rapidly to blindness. The Cherry-red spot is a typical funduscopic finding. Seizures usually begin near the end of the first year and progressively worsen. Further deterioration in the second year of life results in decerebrate posturing, swallowing difficulties and finally an unresponsive vegetative state. Death usually occurs before the age of four.

Cherry-Red Spot in Tay-Sachs Disease

Juvenile-onset Tay-Sachs disease begins with ataxia and incoordination between age two and ten years. By the end of the first decade, most patients endure spasticity and seizures, then, develop decerebrate rigidity and vegetative state. Patients generally succumb to the disease in the two decades.

Some HEXA alleles have some residual activity and lead to Adult-onset forms of Tay-Sachs. Adult-onset Tay-Sachs disease has various courses. Cognitive dysfunction and dementia can be observed. As many as 40% of individuals have psychiatric manifestations without dementia. Vision is rarely affected. Some patients develop progressive dystonia, muscle wasting, weakness, and spinocerebellar degeneration.

Pseudodeficiency

A pseudodeficiency allele is a variation that alters the protein product or changes the gene’s expression, but without causing disease. Two pseudodeficiency alleles are clinically benign and one pseudodeficient allele and one disease-causing allele also do not lead the disease. These individuals have low-level of Hexosaminidase A activity (about %20 of normal enzyme levels) and that is sufficient to prevent GM2 ganglioside accumulation in the cell.

Concluding

Tay-Sachs disease is a fatal, pan-ethnic, autosomal recessive disease that characterized by progressive neuron death. Although Tay-Sachs disease has no cure, screening of high-risk populations for carriers and subsequent prevention has reduced the incidence of Tay-Sachs disease among Ashkenazi Jews by nearly %90.

Sources and further reading

1) Bley, A. E., Giannikopoulos, O. A., Hayden, D., Kubilus, K., Tifft, C. J., & Eichler, F. S. (2011). Natural history of infantile G(M2) gangliosidosis. Pediatrics128(5), e1233-41.

2) Lawson CA, Martin DR. Animal models of GM2 gangliosidosis: utility and limitations. Appl Clin Genet. 2016 Jul 20;9:111-20. doi: 10.2147/TACG.S85354.eCollection 2016. Review. PubMed PMID: 27499644; PubMed Central PMCID: PMC4959762.

3)https://www.omim.org/entry/272800

4)https://www.ncbi.nlm.nih.gov/books/NBK1218/


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