Sandhoffs disease

Methylmalonic aciduria (Bi2-reslstant) Mucolipidosis II (I-cell disease) Nlemann-Plck disease Sandhoff disease... 

P5. Prence, E. M., Jerome, C. A., et al, Heterozygosity for Tay-Sachs and Sandhoff diseases among Massachusetts residents with French Canadian background. J. Med. Screen 4(3), 133-136... 

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. 

GM2-gangliosidosis, O-variant, Sandhoff disease 268800 -Hexosaminidase A and (EC 3.2.1.52) L, F, P, D GM2-ganglioside, GA2 (asialio-GM2)-ganglio-side, globoside U (oligosaccharides)... 

These enzymes are deficient in GM2-gangliosidosis, -variant (Sandhoff disease Table 4.4.1, Fig. 4.4.1). The assay is based on the method described by O Brien et al. [40]. 

Chamoles NA, Blanco M, Gaggioli D, Casentini C (2002) Tay-Sachs and SandhofF diseases enzymatic diagnosis in dried blood spots on filter paper retrospective diagnoses in newbornscreening cards. Clin Chim Acta 318 133-137... 

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... 

Sandhoff disease Hexominidase a and b gm2 gangliosides Neurological Mouse Plasmid IV (Yamaguchi et al., 2003) Ad Intracerebral (Bourgoin et al., 2003)... 

Yamaguchi, A., Katsuyama, K., Suzuki, K, Kosaka, K., Aoki, I. and Yamanaka, S. (2003). Plasmid-based gene transfer ameliorates visceral storage in a mouse model of Sandhoff disease. J. Mol. Med. 81, 185-193. 

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. 

Sandhoff disease G M2 gangliosidosis p-subunit p-hexosaminidase 5ql3... 

Gm2 gangliosidosis is caused by a deficiency of hexosamidase A and B. It was described for the first time by K.. Sandhoff et al. as Sandhoffs disease in 1968. This biochemical variant (type II) largely corresponds to Tay-Sachs disease, which is also autosomal recessive. Renal globoside (ceramide trihexoside) is stored in the visceral organs, particularly in the liver and spleen. Hepatomegaly is present, occasionally with splenomegaly. The lysosomes within the hepatocytes become considerably larger until they are as big as the nucleus and show lamellar structures. 

Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A, Westphal H, McDonald MP, Crawley JN, Sandhoff K, Suzuki K, Proia RL (1995) Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and gan-glioside metabolism. Nat Genet 11 170-176... 

Sango K, Takano M, Ajiki K, Tokashiki A, Arai N, Kawano H, Horie H, Yamanaka S (2005) Impaired neurite outgrowth in the retina of a murine model of Sandhoff disease. Invest Ophthalmol Vis Sci 46 3420-3425... 

Andersson U, Smith D, Jeyakumar M, Butters TD, Borja MC, Dwek RA, Platt FM (2004) Improved outcome of N-butyldeoxygalactono-jirimycin-mediated substrate reduction theraphy in a mouse model of Sandhoff disease. Neurobi-olDis 16 506-515... 

Several lysosomal storage diseases result from defective expression of specific glycosidases. The intracellular accumulation of unprocessed carbohydrate substrates leads to aberrant cellular structure and cell death. Thus, deficient or defective hexosaminidase results in either Tay-Sachs or Sandhoff disease [157]. Fucosidosis, another neurovisceral storage disease, is caused by defective a-L-fucosidase expression. 

GM2 gangliosidosis is a family of autosomal recessive disorders characterized by accumulation of GM2 ganglioside and its related glycolipids in the neuronal lysosome. It comprises GM2 activator protein deficiency, Tay-Sachs and Sandhoff disease, the latter of which are caused by a deficiency in the a-subunit or B-subunit of B-hexosaminidase, respectively (Gravel et ah, 1995). 

The deficiency in hexosaminidase A and B occurring in Sandhoff disease results in accumulation of GM2 and GA2 primarily in the lysosomes of neuronal cells (Fig. 17.3), leading to the formation of membranous cytoplasmic bodies (MCBs) (Tutor, 2004). 

Bone marrow transplantation of Sandhoff disease mice does not reduce GM2 storage levels in the brain but does lead to the prevention of microglial activation and thus neuronal death (Norflus et al., 1998). Therefore, the inflammatory process may play a key role in the pathogenesis of GM2 gangliosidoses. 

In our laboratory an authentic in vitro cellular model for Sandhoff disease has been generated upon treatment of RAW264.7 murine macrophages with an inhibitor of p-hexosaminidase (Boomkamp and Butters, unpublished data). High performance liquid chromatography (HPLC) analyses of extracted GSL oligosaccharides show that GA2 predominantly accumulates in inhibitor-treated RAW cells as opposed to a minor but significant increase in GM2 levels (Fig. 17.7). This difference in elevation is possibly due to the... 

Overall, the developed in vitro RAW model is an authentic, cellular representative of Sandhoff disease and may provide further insights into the disease pathology and for evaluating potential therapies for this disorder. 

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... 

Huang, J. Q., Trasler, J. M., Igdoura, S., Michaud, J., Hanal, N., and Gravel, R. A., Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. Hum Mol Genet 6 (1997) 1879-1885. 

Jeyakumar, M., Butters, T. D., CortinaBoija, M., Hunnam, V., Proia, R. L., Perry, V. H., Dwek, R. A., and Platt, F. M., Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin, Proc Nat Acad Sci USA 96 (1999) 6388-6393. 

Norflus, F., Tifft, C. J., McDonald, M. P., Goldstein, G., Crawley, J. N., Hoffmann, A., Sandhoff, K., Suzuki, K., and Proia, R. L., Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice, J Clin Invest 101 (1998) 1881-1888. 

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