Tay-Sachs disease hexosaminidases

Tay-Sachs disease Hexosaminidase A Cer—Gic—Gal(NeuAc)-i-GalNAc GM2Gangiioside Mental retardation, blindness, muscular weakness. 

Leukodystrophy Tay-Sachs disease Hexosaminidase A Okada and O Brien (1969)... 

GM2 gangliosidosis (also known as Tay-Sachs disease) is a rare disorder caused by mutations in the gene encoding the lysosomal, heterodimeric ss-hexosaminidase... 

The biochemical defect In Tay-Sachs disease is an inherited deficiency of -hexosaminidase, a lysosomal enzyme responsible for hydrolysis ofGM2 ganglioside, which accumulates abnormally in the lyso-somes. 

Dl. Desnick, R. J., Tmex, J. H., et al., A fully automated method for identification of Tay-Sachs disease carriers by tear beta-hexosaminidase assay. Prog. Clin. Biol. Res. 18, 245—265 (1977). 

In cases of missing //-hexosaminidase activity (Sandhoff disease), the detected acetyl CoA a-glucosaminide N-acetyltransferase activity will be low because liberation of the fluorophore is the rate-limiting step. Therefore, low measured activity of acetyl-transferase with normal / -galaclosidase activity should always trigger an assessment of the //-hexosaminidase activity from the same material. In contrast, missing jS-hex-osamindase A activity (Tay-Sachs disease) does not impede the assay. 

O Brien JS, Okada S, Chen A, Fillerup DL (1970) Tay-Sachs disease. Detection of heterozygotes and homozygotes by serum hexosaminidase assay. N Engl J Med 283 15-20... 

For example, Niemann-Piclc disease is caused by a rare genetic defect in the enzyme sphingomyelinase, which cleaves phosphocholine from sphingomyelin. Sphingomyelin accumulates in the brain, spleen, and liver. The disease becomes evident in infants, and causes mental retardation and early death. More common is Tay-Sachs disease, in which ganglioside GM2 accumulates in the brain and spleen (Fig. 2) owing to lack of the enzyme hexosaminidase A. The symptoms of Tay-Sachs disease are progressive retardation in development, paralysis, blindness, and death by the age of 3 or 4 years. 

The best known and the commonest sphingolipi-dosis is Tay-Sachs disease.366-368 Several hundred cases have been reported since it was first described in 1881. A terrible disease, it is accompanied by mental deterioration, blindness, paralysis, dementia, and death by the age of three. About 15 children a year are born in North America with this condition, and the world figure must be 5-7 times this. The defect is in the a subunit of the (3-hexosaminidase A (point 7 in Fig. 20-10)366,366a with accumulation of ganglioside GM2- Somewhat less severe forms of the disease are caused by different mutations in the same gene369 or in a protein activator. Sandhoff disease, which resembles Tay-Sachs disease, is caused by a defect in the (3 subunit, which is present in both P-hexosaminidases A and B.368 Mutant "knockout" mice that produce only ganglioside GM3 as the major ganglioside in their central nervous system die suddenly from seizures if they hear a loud sound. This provides further evidence of the essential nature of these components of nerve membranes.3693... 

There is no way of treating Tay-Sachs disease. Enzyme replacement is not considered a likely therapy because infused enzyme cannot penetrate the blood-brain barrier. However, the incidence of the disease has been dramatically decreased by prenatal diagnosis. Tay-Sachs disease is an autosomal recessive disease and so can arise only if both parents are carriers, i.e., if each parent carries a single defective gene for the hexosaminidase A enzyme. In that case there is a 25% chance that a child of these parents will have the disease. 

If both parents carry a single defective gene for the hexosaminidase A enzyme, there is a 25% chance that their child will have Tay-sachs disease. What chance is there that their child would be a carrier of a defective gene ... 

Guidotti, J. E., Mignon, A., Haase, G., Caillaud, C., McDonell, N., Kahn, A. and Poenaru, L. (1999). Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice. Hum. Mol. Genet. 8, 831-838. 

Lacorazza, H. D., Flax, J. D., Snyder, E. Y. and Jendoubi, M. (1996). Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat. Med. 2, 424-429. 

Genetic diseases can be divided into two main groups based on whether they are caused by relatively few common mutations or by many unique mutations. Tay-Sachs disease, a fatal neurodegenerative disorder caused by a deficiency of hexosaminidase A, is common in the Ashkenazi Jewish population. Three hexosaminidase mutations account for 96% of the disease in the Ashkenazi Jewish population (9). In contrast most patients with Fabry disease, a metabolic disorder caused by deficiency of the enzyme galactosi-dase A, have unique mutations in the galactosidase A gene (10). This... 

Tay-Sachs disease. A member of a family of disorders identified as the Gm2 gangliosidoses. As neural cell membranes are enriched in Gm2 gangliosides, the inability to degrade this class of sphingolipid resnlts in neural cell death. In addition to Tay-Sachs disease the family includes the Sandhoff diseases and the Gm2 activator deficiencies. Tay-Sachs disease resnlts from defects in the HEXA gene encoding the a-subunit of /3-hexosaminidase. 

Tay-Sachs disease is the B-variant of GM2 gangliosidosis due to a-chain deficiency and to the subsequent deficiency of hexosaminidases A and S, buf wifh normal hexosaminidase B. Depending on fhe residual enz)me acfivify of /3-hexosaminidase, fhe onsef of symptoms may occur an)Twhere from late infancy to adulthood and are usually subclassifled into infantile (t) e 1)-, juvenile (type 2)-, chronic-, and adult-onset forms [33]. In type 1, the most common disease with a carrier frequency of 1 in 27 among Ashkenazi Jews [154], patients are normal at birth but then show s)mptoms, such as mild motor weakness, between 3 and 6 months, resulting in hypotonia, poor head control, decreasing attentiveness, and visual symptoms (cherry red... 

E. Because a hexosaminidase is deficient in Tay-Sachs disease, partially degraded sphin-golipids (gangliosides) accumulate in lysosomes. 

Tay-Sachs disease can be diagnosed in the course of fetal development Amniotic fluid is obtained by amniocentesis and assayed for p-N-acetyl-hexosaminidase activity. 

Tay-Sachs disease is a fatal genetic disorder where harmful amounts of lipids called ganglioside accumulate in the nerve cells and brains of those affected. Infants with this disorder appear normal for the first several months of life, and then as the lipids distend the nerve cells and brain cells, progressive deterioration occurs the child becomes blind, deaf, and eventually unable to swallow. Tay-Sachs disease occurs mainly in Jewish children of Eastern European descent, and death from bronchopneumonia usually occurs by age 3 to 4 years. A reddish spot on the retina also develops, and symptoms first appear around 6 months of age. It is a lysosomal storage disorder with insufficient activity of the enzyme hexosaminidase A, which catalyzes the biodegradation of the gangliosides. The diagnosis is made by the clinical suspicion and serum hexosaminidase level. Currently there is no treatment available for this disease. 

Tay-Sachs disease A genetic disease that is a result of a deficiency in hexosaminidase A (P-A-acetylhexosaminidase), an enzyme that is involved in the degradation of ganghosides in the lysosome. The disease is prevalent in Jewish children of Eastern European descent and leads to a buildup of ganghoside in nerve cells of the brain and neuronal dysfunchon. 

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