Deficiency, hexosaminidase A

Deficiency of the enzyme hexosaminidase A, the cause of Tay-Sachs disease. Hex-A deficiency results in failure to process a lipid (a fat) which accumulates and is deposited in the brain and other tissues, to their detriment. The lipid that is deposited is called GM2-ganglioside. The deposition of GM2-ganglioside, in turn, produces Tay-Sachs disease (TSD), a genetic disorder in which there is progressive degeneration of the central nervous system including the brain. The classic infantile form of TSD is usually fatal by age 5 years. It has an insidious onset in infancy. The child develops normally for the first few months of life. An exaggerated startle reaction may first be noted. Head control is lost by 6-8 months of age. The infant cannot roll over or sit up. Spasticity and rigidity develop. Excessive drooling and convulsions become evident. Blindness and head enlargement set in by the second year. After age 2, total constant nursing care is needed. Death is due usually to cachexia (wasting away) or aspiration pneumonia initiated by food going down “the wrong way” into the lungs. There are forms of TSD with somewhat more hex-A and later onset of symptoms. These forms are termed juvenile TSD and adult TSD, respectively. All forms of hex-A deficiency are inherited in an autosomal recessive fashion. The gene for Hewx-A is on a nonsex (autosomal) chromosome, specifically on chromosome 15 in region 15q23-q24. A person with 2 copies of the gene has TSD whereas someone with 1 copy is a carrier with no ill effects. TSD is a model of a fatal metabolic disease that occurs primarily within a well-defined population. The frequency of TSD is much higher in Ashkenazi Jews (those of European origin) than in other groups of Jews. In the U.S., 95% of Jews are Ashkenazi and are at risk for TSD. TSD occurs much more rarely in non-Jews. The biochemical basis of TSD has permitted screening programs for carrier detection and prenatal diagnosis of TSD. The disease is named for the English physician Waren Tay (1843-1927) and the New York neurologist Bernard (Barney) Sachs (1858-1944). Tay in 1881 studied an infant with progressive neurological impairment and described “symmetrical changes in the yellow spot in each eye”, the “cherry-red spots” characteristic of TSD. Sachs saw a child In 1887 and the child’s sister in 1898 with the cherry-red spots and “arrested cerebral development” and in 1910 he demonstrated the presence of accumulated lipid in the brain and retina.