Gangliosides accumulation

A (Hex A) catalyzing the biodegradation of gangliosides. Accumulation of gangliosides in lysosomes primarily affects brain neurons. In the early onset form of the disease, children become blind, deaf, and unable to swallow. Children die usually before the age of three. A late onset form ofthe disease occurs in young adults and is usually nonfatal. 

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

Gjy[3 ganglioside accumulates most frequently other compounds occasionally. 

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. 

Small molecule therapeutics are generally more able to access the neural tissue and the efficacy of miglustat to reduce neuronal cell ganglioside accumulation in murine models of Tay-Sachs and Sandhoff disease, indicates that a proportion of the plasma dose reaches the CNS. Direct measurement of... 

In which compartment of the cell does ganglioside accumulate in Tay-Sachs patients What is the biochemical defect ... 

P- N-Acetylhexosaminidase A (EC 3.2.1.30). In type B, the enzyme is absent. In type AB, the enzyme is present but an activator protein is absent. In type A B, the enzyme is present but defective. Gm2 accumulates intraneuronally in white and gray matter of the brain, with small quantities in spleen and liver. Clinical picture and prognosis similar to infantile form of Sandhoffs disease, with manifestation at 4-6 months (ganglioside accumulation begins in utero). 

Several diseases—Gaucher s, Tay-Sachs, Niemann-Pick, and Fabry s diseases, and the leukodystrophies— are characterized by accumulation of lipoid material in cells. These diseases differ in the composition and site of the lipoid accumulation. Whereas gangliosides accumulate in Tay-Sachs disease, sphingosides are found in Niemann-Pick disease, and cerebrosides in... 

Gaucher s disease. Gangliosides accumulate primarely in the cells of the nervous system, but sphingosides and cerebrosides pile up in the reticuloendothelial cells [108, 109]. 

Whether such a block constitutes the only mechanism by which ganglioside accumulates in brain is by no means certain. In fact, reports have appeared claiming an accumulation of the ceramide tetrasaccharide complexes (A and C) in some cases of Tay-Sachs disease. Furthermore, the coexistence of Tay-Sachs disease and abnormal gangliosides cannot be excluded (see above). Brain lipoidosis, like glyco-genesis, could result from several different metabolic alterations. 

One theory (Doss and Matiar-Vahar 1965) states that gangliosides accumulate in the brain of HD patients, because the ganglion cell has no other way to metabolize polysaccharide fragments except using them for ganglioside synthesis. However, it is unlikely that increased formation of gangliosides would lead to their accumulation in the absence of a simultaneous disturbance of the degrading system or of impairment of a feedback mechanism. 

An inborn error of lipid storage. The most common form of the disease is due to a deficiency of ganglioside GM2-hex-osaminidase, an enzyme which catalyses the breakdown of ganglioside GM2. As a result, this ganglioside accumulates in nervous tissue. Paralysis, dementia and blindness are features of the condition. Death occurs in early infancy. 

Hahn, C.N. del Pilar Martin, M. Schroder, M. Vanier, M.T. Hara, Y. Suzuki, K. Suzuki, K. d Azzo, A. Generalized CNS Disease and Massive Gmi-Ganglioside Accumulation in Mice Defective in Lysosomal Acid P-Galactosidase. Hum. Mol Genet 1997, 6, 205-211. 

Snyder, P. D., Jr., Krivit, W., and Sweeley, C. C., 1972, Generalized accumulation of neutral glycosphingolipids with GM-ganglioside accumulation in the brain, J. Lipid Res. 13 128-136. 

---