B variant GM2-gangliosidosis

This disorder known as Tay-Sachs disease (TSD) is concisely defined by OMIM (Online Mendelian Inheritance in Man) as “an autosomal recessive, progressive neurodegenerative disorder, which in the classic infantile form, is usually fatal by age 2 or 3 years, results from deficiency of the enzyme hexosaminidase A. “Autosomal” points to the gene for TSD residing on a nonsex (autosomal) chromosome (namely, chromosome15q23-q24). “Recessive” indicates a person with 2 copies of the gene has TSD whereas someone with 1 copy is a carrier in normal health. TSD worsens, with time, as the central nervous system progressively deteriorates. The “classic” (“textbook”) type of TSD has its insidious onset in infancy. The child with TSD usually 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. “Fatal by age 2 or 3 years” today would be modified to “fatal by age 5.” 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. TSD is due to deficiency of an enzyme (a protein needed to catalyze a specific chemical reaction within the body). Lack of the enzyme which results in failure to process a lipid (a fat) which accumulates and is deposited in the brain and other tissues, to their detriment. The enzyme is called hexosaminidase-A (hex-A) and the lipid that is deposited is called GM2-ganglioside. TSD is a model of a fatal metabolic disease that occurs primarily within a well- defined subpopulation. It is one of several genetic diseases found more often in persons of Jewish origin. (Other Jewish genetic diseases include Gaucher disease, Niemann-Pick disease, Bloom syndrome, and factor XI defiency). The frequency of TSD is much higher in Ashkenazi Jews (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 more rarely, in non-Jews. Knowledge of the biochemical basis TSD has permitted screening programs for carrier detection and prenatal diagnosis of TSD. There are forms of TSD with somewhat more hex-A and hence later onset, termed juvenile TSD and adult TSH. Alternative names for TSD itself are amaurotic familial idiocy (outdated), hexosaminidase A deficiency, hex-A deficiency. TSD 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.