Tay-Sachsoverview

= Tay-Sachs Disease =

Overview
Tay-Sachs disease (TSD), also known as B variant GM2 gangliosidosis, GM2 gangliosidosis type 1, TSD, or Sphingolipidoses, is a rare, autosomal recessive genetic disease. Although Tay-Sachs does have a late onset version that effects adults, the primary variant of TSD, infantile Tay-Sachs disease, effects very young children, causing a deterioration of nerve cells, resulting in a progressive impairment of mental and physical abilities. The effects of the disease usually begin to manifest around six months of age and ultimately result in death, usually by age four.

Although the disease is a parent's worst nightmare, resulting in the live birth of a seemingly healthy child before systematically dismantling their brain and nervous system like a biblical curse, it is extremely rare. The incidence of TSD in the United States is 1 in 320,000. However, some ethnic backgrounds have much higher incidences. The Ashkenazi Jews have a much higher incidence of TSD, as well as other lipid storage diseases. It is estimated that 1 in every 3,500 newborn Ashkenazi Jews are born with Tay-Sachs, making them nearly 1000 times more likely to have TSD than the general American population. French Canadians from Quebec and Cajuns in Louisiana also have much higher occurrences of TSD, similar to the Ashkenazi.

TSD is caused by a recessive trait mutation of the HEXA gene located on human chromosome 15. Various mutations of HEXA that cause TSD have been identified, with more being discovered through various genetic and molecular techniques. Many of the documented mutant variants have been discovered to occur in significant frequencies in specific populations, meaning that although the disease manifests itself in the same way across populations, the underlying mutations that cause the deficiency resulting in the disease are very different in different ethnic lineages. The mutations identified in Ashkenazi Jews are different than those found in Cajun populations, and, in turn, different than those found in French Canadian, and different still from those identified in Irish Americans.

History [[image:Bernardsachs2.jpg align="right" caption="Bernard Sachs (Image from Public Domain; No permission required)"]]
TSD was first described by Waren Tay and Bernard Sachs, two medical doctors for which the disease is named. Waren Tay, a British opthalmologist, first described the characteristic symptomatic cherry red spot on the retina of the eye in 1881, a preliminary diagnostic indicator still used today. Bernard Sachs, a neurologist working at Mount Sinai Hospital in New York, first discovered the link to Ashkenazi Jews in the 1880s, before the renaissance of Gregor Mendel's classical genetics theories, and nearly a century before modern genetics and genomic research. Sachs also first described the cellular changes involved in TSD in 1887. Sachs is also responsible for the original name of the disease, amaurotic familial idiocy.

It was not until 1969 that is was discovered that TSD was the result of an enzyme defect, a result of hexosaminidase deficiency. Shintaro Okada and John S. O'Brien were the first to note this, and developed a diagnostic hexosaminidase activity assay, making it one of the first diseases to be researched and diagnosed at a molecular level, paving the way for many scientific technological advances. This made newborn testing, carrier screening, and prenatal diagnosis possible in the 1970s. By the end of the 1970s, TSD was definitively described as a GM2 gangliosidosis, a group of genetic disorders resulting from enzyme beta-hexosaminindase deficiency, with three variants being discovered: TSD, AB variant, and Sandhoff disease. All three diseases are characterized by a failure in the same metabolic pathway leading to the same outcome, making them hard to distinguish clinically from each other. Sandhoff disease actually has the exact same clinical symptoms as TSD, but is actually the result of a mutation of the HEXB gene located on chromosome 5, an entirely different chromosome than HEXA. AB variant is easier to distinguish because the disease is actually caused by a mutation of the GM2A gene, which codes for a cofactor for beta-hexosaminidase, not for the enzyme itself.

Back to Tay-Sachs (Home)

HEXA Gene

Hexosaminidase A

HEXA Protein Interactions

Phylogenetic Analysis