Gm2 gangliosidosis

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

Fig. 4.2.3 TLC of urinary oligosaccharides. Left to right standards (as in Fig. 4.2.2), a normal control, a-mannosidosis, fucosidosis, GM2 gangliosidosis type Sandhoff and aspartylglucos-...

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)... 

This enzyme is deficient in GM2-gangliosidosis, -variant (Tay-Sachs disease Table 4.4.1, Fig. 4.4.1). The assay is based on the method described by Inui and Wenger [23]. 

Sandhoff Jatzkewitz, GM2 gangliosidosis type II 3-N-Acetylhexosaminidase A and B GalNAc-Gal-Gal-Glc-Cer GbOse4Cer... 

Tay Sach s, GM2 gangliosidosis type I 3-N-Acetylhexosa minidase A Gal-Nac-Gal-Glc-Cer NeuAc GM2... 

Compound 14 may be isolated from the urine of patients with Sand-hoff s disease (GM2-gangliosidosis variant O).62 Fundamentally, it is a diantennary oligosaccharide bearing an additional, so-called intersecting GlcNAc residue (9), /3-(l—>4)-l inked to Man-3. The 500-MHz, H-n.m.r. spectrum of 14 is given in Fig. 15, and the n.m.r. data are presented in Table VII. 

Figure 16-5. The pathway of sphingolipid catabolism. Diseases that result from specific enzyme deficiencies are as follows (1) GM, gangliosidosis (2) GM2 gangliosidosis (Tay-Sachs disease) (3) sialidosis (4) Fabry disease (5) Gaucher disease (6) Niemann-Pick disease (7) Krabbe disease (8) metachromatic leukodystrophy (9) Farber disease. Cer, Ceramide Glc, glucose Gal, galactose GalNAc, A -acetylgalactosamine NANA, N-acetyfiieuraminic acid.

An experimental approach that avoids concerns about the quality of brain tissue is to study in available peripheral tissues genes or gene products that are identical to those in neural tissues. Examples include blood cells and cultured skin fibroblasts, and to a lesser extent biopsies of other tissues such as muscle (Bubber et al., 2005). Most workers assume that genes are identical in all tissues examined from an individual but worry about epigenetic modifications, to DNA as well as to post-translational and posttranscriptional products. However, extensive data indicate that study of proteins in peripheral tissues can often give critical information about those molecules in the brain the standard A striking example is the use of white blood cells and cultured skin fibroblasts to elucidate enzyme defects in inborn errors of metabolism. A well-known example is Tay-Sachs disease (GM2-gangliosidosis) (Roe and Shur, 2007). 

Mahuran DJ. Biochemical consequences of mutations causing the GM2 gangliosidoses. Biochim. Biophys. Acta 1999 1455 105-138. Maegawa GH, Tropak M, Buttner J, Stockley T, Kok E, Clarke IT, Mahuran DJ. Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J. Biol. Chem. 2007 282 9150-9161. 

Tropak MB, Mahuran D. Lending a helping hand, screening chemical libraries for compounds that enhance beta-hexosaminidase A activity in GM2 gangliosidosis cells. FEES J. 2007 274 4951-4961. 

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. 

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... 

Martin DR, Cox NR, Morrison NE, Kennamer DM, Peck SL, Dodson AN, Gentry AS, Griffin B, Rolsma MD, Baker HJ (2005) Mutation of the GM2 activator protein in a feline model of GM2 gangliosidosis. Acta Neuropathol 110 443 50... 

Singer HS, Cork LC (1989) Canine GM2 gangliosidosis morphological and biochemical analysis. Vet Pathol 26 114-120... 

Yamato O, Satoh H, Matsuki N, Ono K, Yamasaki M, Maede Y (2004) Laboratory diagnosis of canine GM2-gangliosidosis using blood and cerebrospinal fluid. J Vet Diagn Invest 16 39 4... 

GM2-gangliosidosis is of two types Tay-Sachs disease, due to /3-hexoseaminidase A (Hex-A) deficiency, and Sandhoff s disease, due to deficiency of jS-hexoseaminidase A and B (Hex-A, Hex-B). The relationship between these diseases is based on the subunit composition of the two affected enzymes. Hex-A, a heteropolymer, consists of two a-chains (coded for on chromosome 15), a /S-chain (coded for on chromosome 5), and an activator protein. Hex-B is a tetramer of /6-chains. Mutations at the a-locus give rise to Tay-Sachs disease. A variant form can arise from mutation at the activator protein locus however, it shows normal in vitro Hex-A activity with chromogenic substrates. Mutations at the /6-locus yield Sandhoff s disease and affect Hex-A and Hex-B, both of which contain the /6-subunit. 

Conzelmann, E., and Sandhoff, K., A B variant of infantile GM2 gangliosidosis Deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proc. Natl. Acad. Sci. U.S.A. 75, 3979—3983 (1978). 

GM2 gangliosidosis Tay-Sachs Sandhoff GM2 activator B-hex A B-hex A,B GM2 activator protein GM2, GlcNAc-OS GM2, GA2, GlcNAc-OS GM2 Phospholipids, cholesterol... 

In this chapter the focus will be on the most common LSDs with neurological involvement, Niemann-Pick type C, types II and III Gaucher disease, GMl and GM2 gangliosidosis. 

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 main clinical features of this group of neurodegenerative diseases include startle reaction, hypotonia, psychomotor retardation, blindness and a greatly reduced life span of which the severity and disease onset are dependent on residual enzyme activity (Table 17.2) (Jeyakumar et ah, 2002). All forms of acute, infantile GM2 gangliosidosis are characterized by a total absence of B-hexosaminidase and thus no or hardly any residual enzyme activity, whereas the chronic, juvenile/adult forms have approximately 5%, and asymptomatic... 

Fig. 17.6 Partial GSL degradation pathway. GM2 is degraded by hexosaminidase A (Hex A) in cooperation with GM2 activator protein to form GM3. The presence of a specific sialidase in mice prevents accumulation of this glycohpid in GM2 gangliosidosis and degrades its substrate to GA2, which in turn can be degraded by Hex A or B. GM3 is acted on by sialidase, present in mouse and human, and lactosylceramide (LacCer) is formed which is then further degraded by specific hydrolases...

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. 

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