Tay-Sachs Disease


Tay-Sachs disease (TSD):
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, and the American neurologist Bernard Sachs of Mount Sinai Hospital, New York 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.

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. It became a research and public health model for understanding and preventing all autosomal genetic.
Symptoms


Fundus photograph showing retina changes associated with Tay-Sachs disease.

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms. 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). 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.

• Infantile TSD. Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of 4 or 5.

• Juvenile TSD. Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5–15 years.

• Adult/Late Onset TSD. A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. LOTS is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis. Patients with LOTS frequently become full-time wheelchair users in adulthood, but many live full adult lives if psychiatric and physical difficulties are accommodated. Psychiatric symptoms and seizures can be controlled with medications.
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.


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