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Tay-Sachs disease (abbreviated TSD, also known as GM2 gangliosidosis, Hexosaminidase A deficiency or Sphingolipidosis) is a genetic disorder, fatal in its most common variant known as Infantile Tay-Sachs disease. TSD is inherited in an autosomal recessive pattern. The disease occurs when harmful quantities of a fatty acid derivative called a ganglioside accumulate in the nerve cells of the brain. Gangliosides are lipids, components of cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs disease, is especially common in the nervous tissue of the brain.
The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye in 1881,[1] and the American neurologist Bernard Sachs of Mount Sinai Hospital, New York[2] who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887.
Research in the late 20th century demonstrated that Tay-Sachs disease is caused by a genetic mutation on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in several populations. French Canadians of southeastern Quebec have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. Many Cajuns of southern Louisiana carry the same mutation that is most common in Ashkenazi Jews. Most HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.[3]
Tay-Sachs disease is a rare disease. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common. The importance of Tay-Sachs lies in the fact that an inexpensive enzyme assay test was discovered and subsequently automated, providing one of the first “mass screening” tools in medical genetics.[4] It became a research and public health model for understanding and preventing all autosomal genetic disorders.[5]
Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms.[6] The variant forms reflect diversity in the mutation base.
All patients with Tay-Sachs disease have a “cherry-red” spot, easily observable by a physician using an ophthalmoscope, in the back of their eyes (the retina).[6] This red spot is the area of the retina which is accentuated because of gangliosides in the surrounding retinal ganglion cells (which are neurons of the central nervous system). The choroidal circulation is showing through “red” in this region of the fovea where all of the retinal ganglion cells are normally pushed aside to increase visual acuity. Thus, the cherry-red spot is the only normal part of the retina seen. Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides.
The development of improved testing methods has allowed neurologists to diagnose Tay-Sachs and other neurological diseases with greater precision. Until the 1970s and 80s, when the molecular genetics of the disease became known, the juvenile and adult forms of the disease were not recognized as variants of Tay-Sachs. Post-infantile Tay-Sachs was often mis-diagnosed as another neurological disorder, such as Friedreich ataxia.[10]
The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When Hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and cause problems.[6] Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity. TSD is a recessive genetic disorder, meaning that both parents must be carriers in order to give birth to an affected child. Then, there is a 25% chance with each pregnancy of having a child with TSD. Prenatal monitoring of pregnancies is available.[6]
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